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| C | R | Score | PMID | Date | Au | Ab | Title | Journal |
|---|---|---|---|---|---|---|---|---|
| 1 | 72.84 | 12621391 | 2003.03.20 | + | + | Isozyme-specific induction of low-dose aspirin on cytochrome P450 in healthy subjects. | Clin Pharmacol Ther | |
| XP Chen, ZR Tan, SL Huang, Z Huang, DS Ou-Yang, HH Zhou, | ||||||||
| OBJECTIVE: This study was designed to define the effect of low-dose aspirin administration on the activity of cytochrome P450 (CYP) in normal human subjects. METHODS: Aspirin, 50 mg daily, was given for 14 days to 18 nonsmoking healthy male volunteers. A modified 5-drug cocktail procedure consisting of caffeine, mephenytoin, metoprolol, chlorzoxazone, and midazolam was performed to simultaneously assess in vivo activity of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and CYP3A, respectively. The activities were assessed on 4 occasions including at baseline, after 7 and 14 daily doses of aspirin, and at 7 days after discontinuation of aspirin. Concentrations of parent drugs and corresponding metabolites in biologic samples were assayed by reversed-phase HPLC. RESULTS: Both 7-day and 14-day aspirin intake increased the activity of CYP2C19 significantly, as indicated by 4-hydroxymephenytoin urinary recovery (P <.001). Induction of low-dose aspirin on CYP2C19 was time-dependent. CYP3A activity indices increased moderately but significantly by both 7-day and 14-day aspirin treatment (P <.05), but the percentage changes in CYP3A activity indices were not significant. Low-dose aspirin had no effect on CYP1A2, CYP2D6, and CYP2E1 in vivo activity by either 7-day or 14-day treatment. CONCLUSIONS: The effect of low-dose aspirin on CYPs was enzyme-specific. Both 7-day and 14-day low-dose aspirin induced the in vivo activities of CYP2C19 but did not affect the activities of CYP1A2, CYP2D6, and CYP2E1. The effect of low-dose aspirin on CYP3A activity awaits further confirmation. When low-dose aspirin is used in combination with drugs that are substrates of CYP2C19, doses of the latter should be adjusted to ensure their efficacy. | ||||||||
| 2 | 69.23 | 11061577 | 2000.11.21 | + | + | Combined phenotypic assessment of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase with the "Cooperstown cocktail". | Clin Pharmacol Ther | |
| DS Streetman, JF Bleakley, JS Kim, AN Nafziger, JS Leeder, A Gaedigk, R Gotschall, GL Kearns, JS Bertino, | ||||||||
| BACKGROUND: Simultaneous administration of several probes enhances the utility of phenotyping, but poor specificity, side effects, and use of drugs not approved by the Food and Drug Administration limit the usefulness of prior phenotyping cocktails. OBJECTIVES: To evaluate potential drug-drug interactions associated with use of a cocktail of caffeine, omeprazole, dextromethorphan, and midazolam for simultaneous phenotyping of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase. METHODS: Twelve subjects received caffeine + dextromethorphan, omeprazole, and midazolam (each alone), and a cocktail of caffeine + dextromethorphan + omeprazole + midazolam. Blood samples were collected at 120 minutes for omeprazole and 5/-hydroxyomeprazole, and at 0, 5, 30, 60, 120, 240, 300, and 360 minutes for midazolam. Twelve-hour urine samples were collected for analysis of dextromethorphan, caffeine, and metabolites. RESULTS: The median CYP1A2 metabolic ratio after administration of caffeine + dextromethorphan was not significantly different from that obtained with the cocktail (P = .84). Likewise, the median N-acetyltransferase-2, xanthine oxidase, and CYP2D6 metabolic ratios were not significantly different after cocktail administration (P = .977 for each N-acetyltransferase-2; P = .795 for xanthine oxidase; P = .75 for CYP2D6). The median CYP2C19 metabolic ratio after cocktail administration was not significantly different from that obtained after omeprazole administered alone (P = 1.000). Also, midazolam plasma clearance was not significantly different after cocktail administration compared with that after administration of midazolam alone (P = .708). The only side effect was sedation, which was associated with intravenous midazolam and occurred to a similar extent after both individual and cocktail phenotyping. CONCLUSIONS: These results indicate no pharmacokinetic or pharmacodynamic interactions that would limit the utility of this phenotyping cocktail for simultaneous measurement of the activity of multiple drug-metabolizing enzymes. | ||||||||
| 3 | 68.52 | 11061580 | 2000.11.21 | + | + | In vivo modulation of CYP enzymes by quinidine and rifampin. | Clin Pharmacol Ther | |
| RA Branch, A Adedoyin, RF Frye, JW Wilson, M Romkes, | ||||||||
| BACKGROUND: The metabolism of drugs and other xenobiotics is mediated by enzymes whose activities can be modulated by different compounds. The activities of these modulators have the potential to be used to optimize drug action, prevent toxicity, or identify the enzymes involved in a reaction. This approach requires that selective agents be used for specific enzymes. However, selectivity of action has been poorly characterized in vivo. METHODS: This study investigated the effect of 3 and 28 days of treatment with quinidine (200 mg daily) and rifampin (INN, rifampicin) (600 mg daily) on the activities of four cytochrome P450 enzymes and N-acetyltransferase in 28 healthy young male volunteers divided into three groups with a cocktail of drug probes used, including caffeine, mephenytoin, debrisoquin (INN, debrisoquine), and dapsone. RESULTS: Quinidine selectively and almost completely inhibited the activity of CYP2D6 from day 3 through day 28 without affecting any other enzymes. Rifampin showed evidence of time-dependent induction of the activities of all measured oxidative routes of metabolism but decreased the acetylation ratio in fast acetylators. The quinidine/rifampin combination resulted in selective CYP2D6 inhibition and induction of all other enzymes evaluated over this time period, suggesting that predictable complex interactions occur with the drug combination. CONCLUSIONS: These observations illustrate the value of simultaneous assessment of the effect of modulators on the activities of multiple specific enzymes with the drug cocktail approach. | ||||||||
| 4 | 68.40 | 16041240 | 2005.10.18 | + | + | Three haplotypes associated with CYP2A6 phenotypes in Caucasians. | Pharmacogenet Genomics | |
| M Haberl, B Anwald, K Klein, R Weil, C Fuss, A Gepdiremen, UM Zanger, UA Meyer, L Wojnowski, | ||||||||
| The human cytochrome P450 2A6 (CYP2A6) enzyme metabolizes several xenobiotic compounds of clinical or toxicological importance. We aimed to identify genetic variants and major CYP2A6 haplotypes associated with CYP2A6 phenotypic variation. CYP2A6 mRNA level, protein level, activity and haplotypes were determined in Caucasian liver samples via real-time polymerase chain reaction, Western blot, coumarin 7-hydroxylation, DNA sequencing and genotyping, respectively. Phenotypes were then analyzed for associations with haplotypes. CYP2A6 transcript, protein and activity levels were correlated among each other. In 45 African-American, 156 Caucasian, 47 Chinese, 50 Japanese and 47 Korean DNA samples, we detected 95 different polymorphisms in the CYP2A6 gene, 49 of which had not been described previously. Caucasian variants formed 33 haplotypes which built four clades. Allele *9B and the CYP2A7/2A6 partial deletion allele CYP2A6*12B were both associated with decreased expression. The latter haplotype extends at least over 147 kb up into the CYP2B6 gene. A haplotype almost identical to allele *1A was associated with decreased expression and activity of CYP2A6 compared to all other haplotypes. In summary A CYP2A6*1A-like allele, *9B and *12B are major genetic determinants of CYP2A6 phenotype variation in Caucasians. | ||||||||
| 5 | 64.45 | 15242738 | 2005.01.31 | + | + | Characterization of a KCNQ1/KVLQT1 polymorphism in Asian families with LQT2: implications for genetic testing. | J Mol Cell Cardiol | |
| D Sharma, KA Glatter, V Timofeyev, D Tuteja, Z Zhang, J Rodriguez, DJ Tester, R Low, MM Scheinman, MJ Ackerman, N Chiamvimonvat, | ||||||||
| Congenital long QT syndrome (LQTS) is a genetic disease that predisposes affected individuals to arrhythmias, syncope, and sudden death. Mutations in several ion channel genes have been discovered in different families with LQTS: KCNQ1 (KVLQT1, LQT1), KCNH2 (HERG, LQT2), SCN5A (LQT3), KCNE1 (minK, LQT5), and KCNE2 (MiRP1, LQT6). Previously, the P448R-KVLQT1 missense mutation has been reported as an LQT1-causing mutation. In this report, we demonstrate the presence of the P448R polymorphism in two, unrelated Chinese LQTS families. Although absent from 500 reference alleles derived from 150 white and 100 African-American subjects, P448R was present in 14% of healthy Chinese volunteers. Given the inconsistencies between the genotype (LQT1) and clinical phenotype (LQT2) in our two LQTS families, together with the finding that the P448R appears to be a common, ethnic-specific polymorphism, mutational analysis was extended to the other LQTS-causing genes resulting in the identification of distinct HERG missense mutations in each of these two families. Heterologous expression of P448R-KVLQT1 yielded normal, wild-type (WT) currents. In contrast, the two unique HERG mutations resulted in dominant-negative suppression of the WT HERG channel. Our study has profound implications for those engaged in genetic research. Importantly, one child of the original proband was initially diagnosed with LQT1 based upon the presence of P448R-KVLQT1 and was treated with beta-blockers. However, he did not possess the subsequently determined LQT2-causing mutation. On the other hand, his untreated P448R-negative brother harbored the true, disease-causing HERG mutation. These findings underscore the importance of distinguishing channel polymorphisms from mutations pathogenic for LQTS and emphasize the importance of using appropriate ethnically matched controls in the genotypic analysis of LQTS. | ||||||||
| 6 | 63.95 | 16041244 | 2005.10.18 | + | + | Dopamine transporter (SLC6A3) 5' region haplotypes significantly affect transcriptional activity in vitro but are not associated with Parkinson's disease. | Pharmacogenet Genomics | |
| SN Kelada, P Costa-Mallen, H Checkoway, CS Carlson, TS Weller, PD Swanson, GM Franklin, WT Longstreth, Z Afsharinejad, LG Costa, | ||||||||
| The dopamine transporter (DAT) plays a critical role in dopaminergic neurotransmission and is also the major site of action for some drugs of abuse. The coding region of the DAT gene, SLC6A3, is well conserved, but non-coding regions are more variable, most notably a variable number of tandem repeats (VNTR) polymorphism in the 3' untranslated region, which has been studied in a number of dopamine-related neurological disorders, including Parkinson's disease (PD). We aimed to characterize variation in the 5' region of SLC6A3 because little is known about the extent of variation in this region and potential consequences of such variation on gene expression. We identified multiple single nucleotide polymorphisms (SNPs) covering approximately 5000 bp 5' of exon 1 through the start of exon 2 (+2106). These SNPs segregated as eight haplotypes, six of which were common. These haplotypes differed significantly in activity in a reporter gene activity assay. However, we did not observe associations between common SNPs or haplotypes and PD in a case-control study of 261 incident cases and 376 age- and gender-matched unrelated controls. By contrast, we did observe a modest association of the 3' VNTR 9-repeat allele with PD (odds ratio=1.45; 95% confidence interval=1.04-2.03). This association was limited to subjects 60 years of age and greater versus those less than 60 years of age. We conclude that although DAT 5' region SNPs haplotypes significantly alter in vitro transcriptional activity, they are not related to PD risk. In addition, our findings provide further evidence supporting an association of PD with the VNTR polymorphism. | ||||||||
| 7 | 60.20 | 12740916 | 2003.07.17 | + | + | Sequence variations in the DNA repair gene XPD and risk of lung cancer in a Chinese population. | Int J Cancer | |
| G Liang, D Xing, X Miao, W Tan, C Yu, W Lu, D Lin, | ||||||||
| Variation in DNA repair capacity, which is believed to be largely determined by genetic traits, is linked to risk of certain cancers. The Asp312Asn and Lys751Gln polymorphisms in the xeroderma pigmentosum complementary group D (XPD) gene may alter DNA repair capacity. We thus examined the hypothesis that these 2 XPD polymorphisms are associated with risk of lung cancer via a large hospital-based, case-control study among Chinese. The study subjects consisted of 1,006 patients with primary lung cancer and 1,020 age- and sex-matched population controls. XPD genotypes were determined using PCR-RFLP techniques, and the associations between genotypes and risk of lung cancer were estimated by odds ratios (ORs) and their 95% confidence intervals (CIs) calculated by unconditional logistic regression. Subjects homozygous for the 312Asn/Asn genotype had an increased risk of lung cancer (adjusted OR = 10.33, 95% CI = 1.29-82.50) compared with subjects homozygous for the 312Asp/Asp genotype. The 751Gln/Gln genotype was also associated with increased risk for the cancer compared with the 751Lys/Lys genotype (adjusted OR = 2.71, 95% CI = 1.01-7.24). Stratification analysis revealed that the increased risk was mainly confined to lung squamous cell carcinoma, with the ORs being 20.50 (95% CI = 2.25-179.05) for the 312Asn/Asn genotype and 4.24 (95% CI = 1.34-13.38) for the 751Gln/Gln genotype, respectively. Haplotype analysis with the 2 polymorphisms suggested these polymorphisms might be in linkage disequilibrium with a different causative locus or act together with other functional variants in or close to the XPD locus. | ||||||||
| 8 | 59.90 | 9205822 | 1997.09.19 | + | + | Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2. | Br J Clin Pharmacol | |
| SE Ball, D Ahern, J Scatina, J Kao, | ||||||||
| AIMS: In order to anticipate drug-interactions of potential clinical significance the ability of the novel antidepressant, venlafaxine, to inhibit CYP2D6 dependent imipramine and desipramine 2-hydroxylation was investigated in human liver microsomes. The data obtained were compared with the selective serotonin re-uptake inhibitors, fluoxetine, sertraline, fluvoxamine and paroxetine. Venlafaxine's potential to inhibit several other major P450 s was also studied (CYP3A4, CYP2D6, CYP1A2). METHODS: Ki values for venlafaxine, paroxetine, fluoxetine, fluvoxamine and sertraline as inhibitors of imipramine and desipramine 2-hydroxylation were determined from Dixon plots of control and inhibited rate data in human hepatic microsomal incubations. The inhibitory effect of imipramine and desipramine on liver microsomal CYP2D6 dependent venlafaxine O-demethylation was determined similarly. Venlafaxine's IC50 values for CYP3A4, CYP1A2 CYP2C9 were determined based on inhibition of probe substrate activities (testosterone 6 beta-hydroxylation, ethoxyresorufin O-dealkylase and tolbutamide 4-hydroxylation, respectively). RESULTS: Fluoxetine, paroxetine, and fluvoxamine were potent inhibitors of imipramine 2-hydroxylase activity (Ki values of 1.6 +/- 0.8, 3.2 +/- 0.8 and 8.0 +/- 4.3 microM, respectively; mean +/- s.d., n = 3), while sertraline was less inhibitory (Ki of 24.7 +/- 8.9 microM). Fluoxetine also markedly inhibited desipramine 2-hydroxylation with a Ki of 1.3 +/- 0.5 microM. Venlafaxine was less potent an inhibitor of imipramine 2-hydroxylation (Ki of 41.0 +/- 9.5 microM) than the SSRIs that were studied. Imipramine and desipramine gave marked inhibition of CYP2D6 dependent venlafaxine O-demethylase activity (Ki values of 3.9 +/- 1.7 and 1.7 +/- 0.9 microM, respectively). Venlafaxine did not inhibit ethoxyresorufin O-dealkylase (CYP1A2), tolbutamide 4-hydroxylase (CYP2C9) or testosterone 6 beta-hydroxylase (CYP3A4) activities at concentrations of up to 1 mM. CONCLUSIONS: It is concluded that venlafaxine has a low potential to inhibit the metabolism of substrates for CYP2D6 such as imipramine and desipramine compared with several of the most widely used SSRIs, as well as the metabolism of substrates for several of the other major human hepatic P450s. | ||||||||
| 9 | 59.60 | 7663532 | 1995.10.10 | + | + | Phenotyping of CYP2C19 with enantiospecific HPLC-quantification of R- and S-mephenytoin and comparison with the intron4/exon5 G-->A-splice site mutation. | Pharmacogenetics | |
| J Brockmöller, KL Rost, D Gross, A Schenkel, I Roots, | ||||||||
| S-Mephenytoin 4'-hydroxylase (CYP2C19) is a genetically polymorphic cytochrome P450. A modified method for CYP2C19 phenotyping was evaluated in 174 healthy German volunteers and the results were compared with genotyping for the intron4/exon5 G-->A splice site mutation (m1) of CYP2C19, associated with the poor metabolizer (PM) phenotype. A smaller than usual test-dose of 50 mg (R,S)-mephenytoin was used and urine samples were collected from 0 to 5 h and from 5 to 8 h after administration. Trait measurements included the mephenytoin S/R enantiomeric ratio and the hydroxylation index (i.e. the molar ratio of 4'-hydroxy-mephenytoin urinary recovery to the administered S-mephenytoin dose). S- and R-mephenytoin were quantified by isocratic HPLC with a Chiraspher column and 80% n-hexane and 20% dioxane as the mobile phase. All individuals from whom DNA was available (n = 140, including six phenotypically identified PMs) were analysed for the m1 mutation. The population frequency of this CYP2C19 mutation was 0.15. Four individuals were homozygous for m1 having S/R ratios of 0.9 or greater in both intervals of urine collection. Thus, individuals with an S/R ratio > or = 0.9 were classified as PMs and seven of all 174 phenotyped individuals were PMs (4%; 95% confidence limits: 1.6-8.1%). Heterozygous carriers of m1 (n = 34) had a median S/R ratio (5-8 h urine) of 0.06 compared to 0.01 in individuals without this mutation (n = 102; p = 0.0005, Mann-Whitney U-test). No such gene-dose relation was apparent with the hydroxylation index.(ABSTRACT TRUNCATED AT 250 WORDS) | ||||||||
| 10 | 58.70 | 16100023 | 2006.01.12 | + | + | Promoter polymorphisms in the nitric oxide synthase 3 gene are associated with ischemic stroke susceptibility in young black women. | Stroke | |
| TD Howard, WH Giles, J Xu, MA Wozniak, AM Malarcher, LA Lange, RF Macko, MJ Basehore, DA Meyers, JW Cole, SJ Kittner, | ||||||||
| BACKGROUND AND PURPOSE: Endothelial nitric oxide exerts a variety of protective effects on endothelial cells and blood vessels, and therefore the nitric oxide synthase 3 gene (NOS3) is a logical candidate gene for stroke susceptibility. METHODS: We used the population-based Stroke Prevention in Young Women case-control study to assess the association of five NOS3 polymorphisms in 110 cases (46% black) with ischemic stroke and 206 controls (38% black), 15 to 44 years of age. Polymorphisms included 3 single nucleotide polymorphisms (SNPs) in the promoter region (-1468 T>A, -922 G>A, -786 T>C), 1 SNP in exon 7 (G894T), and 1 insertion/deletion polymorphism within intron 4. RESULTS: Significant associations with both the -922 G>A and -786 T>C SNPs with ischemic stroke were observed in the black, but not the white, population. This association was attributable to an increased prevalence of the -922 A allele (OR=3.0, 95% CI=1.3 to 6.8; P=0.005) and the -786 T allele (OR=2.9, 95% CI=1.3 to 6.4; P=0.005) in cases versus controls. These 2 SNPs were in strong linkage disequilibrium (D'=1.0), making it impossible to determine, within the confines of this genetic study, whether 1 or both of these polymorphisms are functionally related to NOS3 expression. Two sets of haplotypes were also identified, 1 of which may confer an increased susceptibility to stroke in blacks, whereas the other appears to be protective. CONCLUSIONS: Promoter variants in NOS3 may be associated with ischemic stroke susceptibility among young black women. | ||||||||
| 11 | 57.74 | 7640151 | 1995.09.18 | + | + | Imipramine metabolism in relation to the sparteine and mephenytoin oxidation polymorphisms--a population study. | Br J Clin Pharmacol | |
| H Madsen, KK Nielsen, K Brøsen, | ||||||||
| 1. Sparteine and mephenytoin phenotyping tests were carried out in 327 healthy Danish subjects. Two weeks later each subject took 25 mg imipramine followed by urine collection for 24 h. The urinary content of imipramine, desipramine, 2-hydroxy-imipramine and 2-hydroxy-desipramine was assayed by h.p.l.c. 2. The medians of the hydroxylation ratios (i.e. 2-hydroxy-metabolite over parent compound) were 6 to 14 times higher in 300 extensive metabolizers of sparteine (EMs) as compared with 27 poor metabolizers (PMs), but none of the ratios separated the two phenotypes completely. 3. There were 324 EM of mephenytoin (EMM) and three PM (PMM) in the sample. The demethylation ratios between desipramine, 2-hydroxy-desipramine and their corresponding tertiary amines showed statistically significant correlations with the mephenytoin S/R isomer ratio (Spearman's rs: -0.20 and -0.27, P < 0.05). 4. The demethylation ratios were higher in 80 smokers than in 245 non-smokers. This indicates that CYP1A2, which is induced by cigarette smoking, also catalyzes the N-demethylation of imipramine. 5. CYP2D6 genotyping was carried out by PCR in 325 of the subjects, and the D6-wt allele was amplified in 298 EMs, meaning that they were genotyped correctly. One PMs was D6-wt/D6-B, another PMs had the genotype D6-wt/ and hence both were misclassified as EMs. The remaining 25 PMs were D6-A/D6-B (n = 5), D6-B/ (n = 18) or D6-D/D6-D (no PCR amplification, n = 2).(ABSTRACT TRUNCATED AT 250 WORDS) | ||||||||
| 12 | 57.15 | 7920695 | 1994.11.18 | + | Interpretation of a simple PCR analysis of the CYP2D6(A) and CYP2D6(B) null alleles associated with the debrisoquine/sparteine genetic polymorphism. | Pharmacogenetics | ||
| AM Douglas, BA Atchison, AA Somogyi, OH Drummer, | ||||||||
| 13 | 56.53 | 11525420 | 2002.03.07 | + | + | Identification of polymorphisms within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder. | Psychiatr Genet | |
| RS Devon, S Anderson, PW Teague, P Burgess, TM Kipari, CA Semple, JK Millar, WJ Muir, V Murray, AJ Pelosi, DH Blackwood, DJ Porteous, | ||||||||
| We have undertaken a search for polymorphic sequence variation within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2 (DISC1 and DISC2), which are both novel genes that span a translocation breakpoint strongly associated with schizophrenia and related psychoses in a large Scottish family. A scan of the coding sequence, intron/exon boundaries, and part of the 5' and 3' untranslated regions of DISC1, plus 2.7 kb at the 3' end of DISC2, has revealed a novel microsatellite and 15 novel single nucleotide polymorphisms (SNPs). We have tracked the inheritance of four of the SNPs through multiply affected families, and carried out case-control association studies using the microsatellite and four common SNPs on populations of patients with schizophrenia or bipolar affective disorder versus normal control subjects. Neither co-segregation with disease status nor significant association was detected; however, we could not detect linkage disequilibrium between all these markers in the control population, arguing that an even greater density of informative markers is required to test rigorously for association in this genomic region. | ||||||||
| 14 | 55.70 | 8097442 | 1993.05.25 | + | + | Molecular basis of genetic variation in debrisoquin hydroxylation in Chinese subjects: polymorphism in RFLP and DNA sequence of CYP2D6. | Clin Pharmacol Ther | |
| SL Wang, JD Huang, MD Lai, BH Liu, ML Lai, | ||||||||
| Debrisoquin hydroxylation phenotype was determined in 124 Chinese persons living in Taiwan, and two poor metabolizers were identified with a urinary metabolic ratio (MR) greater than 12.6. The other subjects, extensive metabolizers, showed a normal frequency distribution of log(MR). Most subjects (50%) showed a 44/29 kb pattern in restriction fragment length polymorphism (RFLP) analysis with use of Xba I, and 30% and 15% of the subjects exhibited a homozygous 29/29 kb and 44/44 kb pattern, respectively. Among extensive metabolizers, subjects with the 44/44 kb pattern had a significant higher log(MR) than those with the 44/29 pattern, and the log(MR) of the subjects with the 44/29 kb pattern was significantly higher than that of the subjects with 29/29 kb pattern. All nine exons and intron 3 of C gamma P2D6 were amplified with polymerase chain reaction (PCR) and sequenced for four extensive metabolizers. Two major polymorphisms were found: one at position 188 of exon 1 and the other at position 4268 in exon 9. With PCR and endonuclease digestion, polymorphisms at exon 1, intron 3, and exon 9 were investigated. Only two of 254 alleles showed a heterozygous guanine at 1934 base pairs (G1934) to adenine (A) mutation, commonly found in white poor metabolizers. Approximately 70% of alleles showed thymine at 188 base pairs (T188), and 76% showed cytosine at 4268 base pairs (C4268) instead of C188 and G4268, as is found in most white subjects. Subjects with T188 or C4268 showed a significant higher log(MR) than subjects with homozygous C188 and G4268. The C/T188, G/A1934, G/C4268, and RFLP polymorphisms may explain the interracial variations between Chinese and white subjects, as well as the genetic variations among Chinese subjects. | ||||||||
| 15 | 55.56 | 12527930 | 2003.08.26 | + | + | High-throughput genotyping by DHPLC of the dihydropyrimidine dehydrogenase gene implicated in (fluoro)pyrimidine catabolism. | Int J Oncol | |
| E Gross, K Seck, S Neubauer, J Mayr, H Hellebrand, A Ratanaphan, V Lutz, H Stockinger, M Kiechle, | ||||||||
| Dihydropyrimidine dehydrogenase (DPD) is the first and rate-limiting enzyme in the degradation of pyrimidines and pyrimidine base analogs including the anticancer drugs 5-fluorouracil (5-FU) and Xeloda. A decreased DPD enzyme activity has been described in cancer patients experiencing severe and life-threatening toxicity after 5-FU treatment and distinct sequence variants in the DPD gene (DPYD) have been associated with impaired enzyme function. The most prominent mutation in the DPD deficient patient group, a mutation in the splicing donor consensus sequence of intron 14, IVS14+1g>a, resulting in a truncated protein, has been observed in the Caucasian population at frequencies as high as 0.91%-0.94%. This underlines the need for a test system for DPYD mutations in patients undergoing chemotherapy with 5-FU or with Xeloda. To set up a fast and sensitive method to identify variant DPYD alleles, we analyzed 50 healthy individuals by denaturing high performance liquid chromatography (DHPLC). A primer set spanning the whole coding region and the exon-intron boundaries of DPYD was used. In addition, a cDNA-based assay was developed to rapidly identify the 165 base pair deletion in the corresponding RNA of IVS14+1g>a mutation carriers. The optimal mutation detection was elaborated for each of the PCR fragments. DHPLC analysis detected 5 different genetic alterations occurring in the coding region of the gene, as well as 10 intronic sequence variants, respectively. In conclusion, high-throughput screening for DPYD variants by DHPLC may be a reliable tool in the investigation of the molecular basis of DPD deficiency. Furthermore, it will help to identify patients at risk for toxic side effects upon chemotherapy using 5-FU and will facilitate individual treatment of patients. | ||||||||
| 16 | 55.47 | 12835614 | 2004.04.14 | + | + | Histamine N-methyltransferase gene polymorphisms in Chinese and their relationship with enzyme activity in erythrocytes. | Pharmacogenetics | |
| GL Chen, H Wang, W Wang, ZH Xu, G Zhou, F He, HH Zhou, | ||||||||
| The aim of this study was to identify polymorphisms in the histamine N-methyltransferase (HNMT) gene in Chinese and to assess their relationship with HNMT activity. One hundred and ninety-two unrelated subjects were recruited. HNMT polymorphisms were screened by direct sequencing with purified polymerase chain reaction products comprising all six exons, plus splice junctions, as well as approximately 2 kb of the 5'-flanking region (5'-FR). Erythrocyte HNMT activity was previously measured by radiochemical microassay. A total of 11 single nucleotide polymorphisms (SNPs) were identified, among which six SNPs had variant allele frequencies greater than 5%. Of the six common SNPs, three (-1637T>C, -463T>C and -411C>T) were located in 5'-FR, one (314C>T) in coding exons, and two (939A>G and 1097A>T) in the 3'-untranslated region (3'-UTR). Most of these common SNPs were in linkage disequilibrium. Genotype-phenotype correlation analyses were performed for those common SNPs in 5'-FR and 3'-UTR. In males, no significant association was found between HNMT activity and these non-coding SNPs. However, in females, the -1637T>C or -463T>C tended to be associated with decreased HNMT activity, whereas the 939A>G or 1097A>T appeared to be correlated with increased enzymatic activity. HNMT polymorphisms differ considerably between Chinese and American. The common SNPs in 5'-FR (-1637T>C and -463T>C) and 3'-UTR (939A>G and 1097A>T) might conditionally regulate the activity of HNMT, or might be genetically linked to unknown mutation(s) underlying the HNMT phenotypic variance. | ||||||||
| 17 | 55.26 | 11585776 | 2001.10.18 | + | + | Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3'-kinase/Akt signaling pathway. | Cancer Res | |
| C Blancher, JW Moore, N Robertson, AL Harris, | ||||||||
| Many oncogenes induce expression of vascular endothelial growth factor (VEGF), a key factor in tumor angiogenesis. Phosphatidylinositol 3'-kinase (PI3K)/Akt is a common signaling pathway for oncogenes and tumor suppressor genes and is involved in VEGF regulation. Because hypoxia is a major stimulus for VEGF production, we examined the effects of LY294002, a selective PI3K inhibitor, on hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression and on endogenous VEGF responses to hypoxia. A panel of breast cancer cell lines reflecting the different genetic changes occurring in human breast cancer was analyzed. LY294002 inhibited HIF-1alpha induction and phosphorylation under hypoxia. However, HIF-2alpha expression was not affected. Basal and hypoxia-inducible VEGF expression was reduced at both mRNA and protein levels by 50%. V12-ras overexpression resulted in an increase in hypoxia-induced HIF-1alpha and HIF-2alpha expression. This effect was blocked by PI3K inhibitor, demonstrating one mechanism for ras synergy with hypoxia-mediated induction of genes. The decreased HIF-1alpha expression was not dependent on VHL interaction because a renal carcinoma cell line with VHL mutation and constitutive high HIF-1alpha expression also showed down-regulation of HIF-1alpha after treatment with LY294002. These results have implications for the use of PI3K inhibitors to inhibit synergistic effects of hypoxia with a wide range of common oncogenes. | ||||||||
| 18 | 55.18 | 9146858 | 1997.07.24 | + | + | Stereoselective 4'-hydroxylation of phenytoin: relationship to (S)-mephenytoin polymorphism in Japanese. | Br J Clin Pharmacol | |
| I Ieiri, K Mamiya, A Urae, Y Wada, M Kimura, S Irie, T Amamoto, T Kubota, S Yoshioka, K Nakamura, S Nakano, N Tashiro, S Higuchi, | ||||||||
| AIMS: The aim of this study was to clarify whether phenytoin (PHT) stereoselective hydroxylation cosegregates with (S)-mephenytoin phenotype. METHODS: A single dose of PHT (100 mg) was administered orally to six healthy Japanese subjects in whom the genotype and phenotype of CYP2C19 had been determined previously. The urinary excretion profiles of the metabolites of PHT, (R)- and (S)-p-HPPH [5-(4-hydroxyphenyl)-5-phenylhydantoin] up to 361 postdose were compared between the two groups of poor metabolizers (PMs, n = 3) and extensive metabolizers (EMs, n = 3) with respect to CYP2C19. CYP2C9 genotype was also determined. RESULTS: All the alleles were found to be wild type (Arg144 Tyr358Ile359Gly417) in each subject. The mean value for cumulative urinary excretion of unchanged PHT was not significantly different between the PMs and the EMs. However, recovery of (R)-p-HPPH at 36 h was 3.5-fold lower and that of (S)-p-HPPH 1.3-fold lower in PMs than in EMs. Although the mean urinary excretion values for both metabolites were significantly lower in the PMs than in the EMs, the difference between the two groups was larger for (R)-p-HPPH. A significant negative correlation was observed between the hydroxylation index of omeprazole (the ratio between the serum concentrations of omeprazole and hydroxyomeprazole in blood samples drawn 3 h after drug intake) and the log10 0-12 h urinary recovery of (R)-p-HPPH. CONCLUSIONS: In humans, the 4'-hydroxylation of PHT is highly stereoselective towards formation of the (S)-enantiomer. Thus, (S)-hydroxylation by CYP2C9 might be the major determinant of the disposition of PHT. However, these results support the hypothesis that the stereoselective hydroxylation pathway of PHT to form (R)-p-HPPH cosegregates with the CYP2C19 metabolic polymorphism. | ||||||||
| 19 | 54.69 | 9757149 | 1998.10.15 | + | + | Effect of fluvoxamine therapy on the activities of CYP1A2, CYP2D6, and CYP3A as determined by phenotyping. | Clin Pharmacol Ther | |
| AD Kashuba, AN Nafziger, GL Kearns, JS Leeder, R Gotschall, ML Rocci, RW Kulawy, DJ Beck, JS Bertino, | ||||||||
| OBJECTIVE: To determine the effect of 150 mg/day fluvoxamine on the activities of CYP1A2, CYP2D6, CYP3A, N-acetyltransferase-2 (NAT2), and xanthine oxidase (XO) by phenotyping with caffeine, dextromethorphan, and midazolam. METHODS: Oral caffeine (2 mg/kg), oral dextromethorphan (30 mg), and intravenous midazolam (0.025 mg/kg) were administered to 10 white male volunteers every 14 days for 4 months and to 10 white premenopausal female volunteers during the midfollicular and midluteal phases of the menstrual cycle for 4 complete cycles (8 total phenotyping measures). The first 6 phenotyping measures were used to establish baseline activity. Subjects were given 150 mg/day fluvoxamine for the fourth month or cycle of the study. Enzyme activity for CYP1A2, CYP2D6, NAT2, and XO was expressed as urinary metabolite ratios. Midazolam plasma clearance was used to express CYP3A activity. RESULTS: No difference between baseline and weeks 2 and 4 of fluvoxamine therapy was observed for NAT2 or XO metabolite ratios. For CYP1A2, CYP2D6, and CYP3A phenotypes, significant differences existed between baseline and fluvoxamine therapy. For CYP1A2, the mean urinary metabolite ratio (+/-SD) was 7.53 +/- 7.44 at baseline and 4.30 +/- 2.82 with fluvoxamine ( P = .012). Mean CYP2D6 molar urinary dextromethorphan ratios before and after fluvoxamine therapy were 0.00780 +/- 0.00694 and 0.0153 +/- 0.0127, respectively (P = .011). Midazolam clearance decreased from 0.0081 +/ 0.0024 L/min/kg at baseline to 0.0054 +/- 0.0021 L/min/kg with therapy (P = .0091). For CYP1A2, CYP2D6, and CYP3A, fluvoxamine therapy changed the phenotyping measures by a median of -44.4%, 123.5%, and -34.4%, respectively. CONCLUSIONS: We concluded that fluvoxamine may cause significant inhibition of CYP1A2, CYP2D6, and CYP3A activity. This metabolic inhibition may have serious implications for a variety medications. | ||||||||
| 20 | 54.40 | 17534875 | 2007.08.30 | + | + | Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan-pharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer. | Cancer | |
| JY Han, HS Lim, YK Yoo, ES Shin, YH Park, SY Lee, JE Lee, DH Lee, HT Kim, JS Lee, | ||||||||
| BACKGROUND: The authors investigated whether ABCB1, ABCC2, and ABCG2 genetic polymorphisms affect pharmacokinetics (PK) of irinotecan and treatment outcome of patients with advanced nonsmall cell lung cancer (NSCLC). METHODS: Blood samples from 107 NSCLC patients treated with irinotecan and cisplatin chemotherapy were used for genotyping ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCC2 (-24C > T, 1249G > A, 3972C > T), and ABCG2 (34G > A, 421C > A) polymorphisms. Genotypes were correlated with irinotecan-PK, toxicity, tumor response, and survival. RESULTS: Among 8 polymorphisms, 3435TT and 2677TT were associated with AUC(SN-38G) and CL(SN-38G). When haplotypes are assigned, 2677TT/3435TT carriers showed significantly lower AUC(SN-38G) (P = .006), whereas 2677GG/3435CC carriers showed significantly higher AUC(SN-38) (P = .039). These findings suggest that 2677TT and 3435TT variants are associated with higher efflux activity. In toxicity, the 2677G/T or A was associated with grade 4 neutropenia. The 2677GG carriers showed significantly lower absolute neutrophil count during the 1(st) cycle (P = .012) as well as entire course of chemotherapy (P = .042). The 3435TT was associated with higher frequency of grade 3 diarrhea (P = .047). In tumor response, ABCC2 -24TT and 3972TT genotypes were associated with higher response rates (P = .031 and .046, respectively) and longer progression-free survival (P = .035 and .038, respectively), which was sustained in haplotype analysis. CONCLUSIONS: Specific polymorphisms of ABCB1 and ABCC2 can influence disposition and tumor response to irinotecan by regulating transporter activity. These findings may help to individualize irinotecan-based chemotherapy in patients with advanced NSCLC. | ||||||||
| 21 | 54.28 | 8747407 | 1996.10.24 | + | + | Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype. | Pharmacogenetics | |
| M Chang, ML Dahl, G Tybring, E Götharson, L Bertilsson, | ||||||||
| A single oral dose of omeprazole (20 mg) was given orally to 160 healthy Caucasian Swedish subjects and tested as a probe for CYP2C19. The study was nonrandomized and included seven subjects previously classified as poor metabolizers (PM) of S-mephenytoin. The ratio between the plasma concentrations of omeprazole and hydroxyomeprazole (metabolic ratio; MR) was determined by HPLC in a blood sample drawn 3 h after drug intake. In 17 subjects the test was repeated and the MRs of omeprazole on the two occasions were correlated (rs = 0.85; p < 0.0001). There was a significant correlation between the MR of omeprazole and the S/R mephenytoin ratio among 141 subjects, in whom both ratios were determined (rs = 0.63, p < 0.001). All seven PMs of S-mephenytoin had higher MRs of omeprazole (7.1-23.8) than extensive metabolizers (EM) (0.1-4.9). All 160 subjects and another 15 Caucasian Swedish PMs previously phenotyped with mephenytoin were analysed with respect to the presence of the CYP2C19m1 allele by PCR amplification of the intron 4/exon 5 junction followed by Sma I digestion. EMs heterozygous for the CYP2C19m1 gene had MRs of omeprazole and S/R ratios of mephenytoin that were higher than those of subjects who were homozygous for the wild-type allele (p = 0.0001). Nineteen of the 22 PMs were homozygous for the CYP2C19m1 gene. Three were heterozygous for this allele. Thus, 41 of the 44 alleles (93%) of PMs were defective CYP2C19m1. One of the remaining three PM alleles was subsequently found to contain the CYP2C19m2 mutation, which has earlier been shown to be associated with the PM phenotype in Oriental populations. In conclusion, the phenotype determined by omeprazole correlated with that of mephenytoin, and was in good agreement with the genotype. | ||||||||
| 22 | 54.06 | 12426569 | 2003.01.17 | + | + | Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. | Nat Genet | |
| K Ozaki, Y Ohnishi, A Iida, A Sekine, R Yamada, T Tsunoda, H Sato, H Sato, M Hori, Y Nakamura, T Tanaka, | ||||||||
| By means of a large-scale, case-control association study using 92,788 gene-based single-nucleotide polymorphism (SNP) markers, we identified a candidate locus on chromosome 6p21 associated with susceptibility to myocardial infarction. Subsequent linkage-disequilibrium (LD) mapping and analyses of haplotype structure showed significant associations between myocardial infarction and a single 50 kb halpotype comprised of five SNPs in LTA (encoding lymphotoxin-alpha), NFKBIL1 (encoding nuclear factor of kappa light polypeptide gene enhancer in B cells, inhibitor-like 1) and BAT1 (encoding HLA-B associated transcript 1). Homozygosity with respect to each of the two SNPs in LTA was significantly associated with increased risk for myocardial infarction (odds ratio = 1.78, chi(2) = 21.6, P = 0.00000033; 1,133 affected individuals versus 1,006 controls). In vitro functional analyses indicated that one SNP in the coding region of LTA, which changed an amino-acid residue from threonine to asparagine (Thr26Asn), effected a twofold increase in induction of several cell-adhesion molecules, including VCAM1, in vascular smooth-muscle cells of human coronary artery. Moreover, the SNP, in intron 1 of LTA, enhanced the transcriptional level of LTA. These results indicate that variants in the LTA are risk factors for myocardial infraction and implicate LTA in the pathogenesis of the disorder. | ||||||||
| 23 | 53.92 | 16041245 | 2005.10.18 | + | + | Influence of the eNOS gene on development of blood pressure and left ventricular mass: longitudinal findings in multiethnic youth. | Pharmacogenet Genomics | |
| H Zhu, X Wang, Y Dong, FA Treiber, H Snieder, | ||||||||
| OBJECTIVES: To evaluate the impact of the endothelial nitric oxide synthase (eNOS) gene on longitudinal development of blood pressure (BP) and left ventricular mass (LVM) from childhood into early adulthood. METHODS: Three polymorphisms including -922A>G, intron 4VNTR, and Glu298Asp of the eNOS gene were investigated. Individual growth-curve modeling and haplotype trend regression analyses were conducted for 579 white and black American youths with 12 assessments over a 15-year period. RESULTS: Significantly different allele and genotype frequencies were observed between blacks and whites for all three polymorphisms. Linkage disequilibrium (LD) patterns among these polymorphisms were also different between ethnic groups: strong LD between the -922A>G and intron 4 VNTR loci was observed in whites but not in blacks. Single locus analyses identified a significant interaction between the intron 4 VNTR and gender on diastolic BP (DBP) levels. The 4a allele carriers had significantly lower DBP levels in males (P=0.012), but higher DBP levels in females (P=0.045). Haplotype analyses confirmed the DBP lowering effect in males (P=0.049). DBP in males homozygous for haplotype G-4a-Glu was 2.58 mmHg lower than males homozygous for the most common haplotype (A-non4a-Glu). Additionally, individuals homozygous for haplotype G-non4a-Glu showed a 0.51 mmHg steeper increase in DBP per year with age as compared to the most common haplotype (P=0.007). No associations between single polymorphisms or haplotypes of the eNOS gene and systolic BP or LVM were found. CONCLUSIONS: our results suggest that eNOS gene may have gender-specific and age-dependent effects on DBP and the development of hypertension risk. | ||||||||
| 24 | 53.91 | 17502835 | 2007.07.20 | + | + | Genetic polymorphisms of CYP2B6 affect the pharmacokinetics/pharmacodynamics of cyclophosphamide in Japanese cancer patients. | Pharmacogenet Genomics | |
| M Nakajima, S Komagata, Y Fujiki, Y Kanada, H Ebi, K Itoh, H Mukai, T Yokoi, H Minami, | ||||||||
| OBJECTIVE: To evaluate the effects of genetic polymorphisms of drug metabolizing enzymes on the pharmacokinetics of cyclophosphamide and its active metabolite, 4-hydroxycyclophosphamide, and on the pharmacodynamics. EXPERIMENTAL DESIGN: One hundred and three Japanese patients with malignant lymphoma or breast cancer treated with cyclophosphamide (500-750 mg/m) participated in this study. The plasma concentrations of cyclophosphamide and 4-hydroxycyclophosphamide were determined by high-performance liquid chromatography, and pharmacokinetic parameters were calculated. The genotypes of CYP2B6, CYP2C19, CYP3A4, CYP3A5, ALDH1A1, GST genes were determined by allele-specific polymerase chain reaction or polymerase chain reaction-restriction-fragment length polymorphism. RESULTS: A large interindividual difference (54-fold) was observed in the area under the curve ratio of 4-hydroxycyclophosphamide/cyclophosphamide calculated as the metabolic index. We first proved that leukocytopenia and neutropenia were significantly (P<0.01) related to the area under the curve of 4-hydroxycyclophosphamide. We found that the homozygotes of CYP2B6*6 (Q172H and K262R) showed significantly (P<0.05) higher clearance and shorter half-life of cyclophosphamide than heterozygotes and homozygotes of CYP2B6*1. The small sample size, however, limited the impact. On the other hand, it was clearly demonstrated that the patients possessing the single nucleotide polymorphisms of the CYP2B6 gene, g.-2320T>C, g.-750T>C (5'-flanking region), g.15582C>T (intron 3), or g.18492T>C (intron 5), had significantly lower area under the curve ratios of 4-hydroxycyclophosphamide/cyclophosphamide, indicating a decreased cyclophosphamide 4-hydroxylation. Of particular importance was the finding that leukocytopenia was significantly related to the single nucleotide polymorphisms g.-2320T>C, g.-750T>C, and g.18492T>C in CYP2B6 gene, which are highly linked. No relationship was observed between the pharmacokinetics of cyclophosphamide or 4-hydroxycyclophosphamide and genetic polymorphisms of the other enzymes. CONCLUSIONS: We clarified that the single nucleotide polymorphisms in the promoter region or introns in the CYP2B6 affect the potency of cyclophosphamide activation to 4-hydroxycyclophosphamide. This information would be valuable for predicting adverse reactions and the clinical efficacy of cyclophosphamide. | ||||||||
| 25 | 53.79 | 15995945 | 2005.09.23 | + | + | Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. | Am J Hum Genet | |
| JS Sutcliffe, RJ Delahanty, HC Prasad, JL McCauley, Q Han, L Jiang, C Li, SE Folstein, RD Blakely, | ||||||||
| Autism is a spectrum of neurodevelopmental disorders with a primarily genetic etiology exhibiting deficits in (1) development of language and (2) social relationships and (3) patterns of repetitive, restricted behaviors or interests and resistance to change. Elevated platelet serotonin (5-HT) in 20%-25% of cases and efficacy of selective 5-HT reuptake inhibitors (SSRIs) in treating anxiety, depression, and repetitive behaviors points to the 5-HT transporter (5-HTT; SERT) as a strong candidate gene. Association studies involving the functional insertion/deletion polymorphism in the promoter (5-HTTLPR) and a polymorphism in intron 2 are inconclusive, possibly because of phenotypic heterogeneity. Nonetheless, mounting evidence for genetic linkage of autism to the chromosome 17q11.2 region that harbors the SERT locus (SLC6A4) supports a genetic effect at or near this gene. We confirm recent reports of sex-biased genetic effects in 17q by showing highly significant linkage driven by families with only affected males. Association with common alleles fails to explain observed linkage; therefore, we hypothesized that preferential transmission of multiple alleles does explain it. From 120 families, most contributing to linkage at 17q11.2, we found four coding substitutions at highly conserved positions and 15 other variants in 5' noncoding and other intronic regions transmitted in families exhibiting increased rigid-compulsive behaviors. In the aggregate, these variants show significant linkage to and association with autism. Our data provide strong support for a collection of multiple, often rare, alleles at SLC6A4 as imposing risk of autism. | ||||||||
| 26 | 53.40 | 15768052 | 2005.08.12 | + | + | Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans. | Pharmacogenomics J | |
| A Gaedigk, A Bhathena, L Ndjountché, RE Pearce, SM Abdel-Rahman, SW Alander, LD Bradford, PK Rogan, JS Leeder, | ||||||||
| Cytochrome P4502D6 (CYP2D6) genotyping reliably predicts poor metabolizer phenotype in Caucasians, but is less accurate in African Americans. To evaluate discordance we have observed in phenotype to genotype correlation studies, select African American subjects were chosen for complete resequencing of the CYP2D6 gene including 4.2 kb of the CYP2D7-2D6 intergenic region. Comparisons were made to a CYP2D6(*)1 reference sequence revealing novel SNPs in the upstream, coding and intervening sequences. These sequence variations, defining four functional alleles (CYP2D6(*)41B, (*)45A and B and (*)46), were characterized for their ability to influence splice site strength, transcription level or catalytic protein activity. Furthermore, their frequency was determined in a population of 251 African Americans. A -692(TGTG) deletion (CYP2D6(*)45B) did not significantly decrease gene expression, nor could any other upstream SNP explain a genotype-discordant case. CYP2D6(*)45 and (*)46 have a combined frequency of 4% and can be identified by a common SNP. Carriers are predicted to exhibit an extensive or intermediate CYP2D6 phenotype. | ||||||||
| 27 | 52.91 | 11802209 | 2002.02.12 | + | + | Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. | Int J Cancer | |
| A Meindl, | ||||||||
| The main focus of this German-wide multi-center study was to establish a BRCA1/2 mutation profile and to determine family types with high frequencies of mutations in these genes. In a comprehensive study, the entire coding sequences of the breast cancer genes BRCA1 and BRCA2 were analyzed in 989 unrelated patients from German breast/ovarian cancer families. A total of 77 BRCA1 and 63 BRCA2 distinct deleterious mutations were found in 302 patients. More than (1/3) of these mutations are novel and might be specific for the German population. Eighteen common mutations were found in 68% of cases in BRCA1 and 13 recurrent mutations in 44% of cases in BRCA2, facilitating prescreening approaches. Haplotype analysis indicate that 14 out of 20 recurrent mutations are likely originating from a common founder. An additional 50 different rare sequence variants with unknown relevance for tumorigenesis were found in 72 families. Correlation of BRCA1/BRCA2 detection rates with family history identified families with both breast and ovarian cancer to be at highest risk for BRCA1/BRCA2 mutations (43% and 10%, respectively), followed by families with at least 2 premenopausal cases of breast cancer (24% BRCA1 and 13% BRCA2 mutations). These data provide strong evidence for further predisposing genes in the German population. In breast cancer families with 2 or 3 affected females but only a single or no premenopausal case, mutations were detected with low frequencies (about 10% or less for both genes). The decision for or against molecular diagnosis is now aided by considering the expected mutation detection rates that greatly depend on family history and structure. | ||||||||
| 28 | 52.45 | 12914384 | 2003.08.28 | + | + | Pharmacogenetics of stomach cancer. | ||
| G Toffoli, E Cecchin, | ||||||||
| Conventionally adjustments of the dose of chemotherapeutic treatment could be uneffective in preventing toxicity and response variability. New strategies for individualization of treatment in cancer patients are becoming an emerging issue in the clinical practice. Pharmacogenetics is undoubtedly an important source of information in this respect deepening the complex correlation existing between individual genetic profile and the response to therapy in terms of toxicity and activity. Several polymorphisms, i.e. genetic mutations with a frequency > 1% in a given population, have been described for genes encoding proteins involved in the metabolism of the drugs employed in the treatment of gastric cancer. TS (thymidilate synthase) and DPD (dihydropyrimidine dehydrogenase) polymorphisms are implicated in the development of toxicity and in the efficacy of 5-fluorouracil (5FU). XRCC1 (X-ray cross-complementing group 1), ERCC1 (excision cross-complementing gene) and GSTP1 (glutathione S-transferase) have a role in the development of pharmacoresistance to platinum derivatives. MTHFR (5, 10 methylenetetrahydrofolate reductase) C677T polymorphism is important in methotrexate (MTX) metabolism. UGT1A1 (uridine diphoshate-glucuronosyltransferase 1A1) is involved on irinotecan metabolism. MRP2 (multi-drug resistance associated protein) and MDR1 (multi-drug resistance gene) are involved in irinotecan as well as anthracyclines transport. In conclusion, the clinical applications of pharmacogenetics could represent a new insight to accurately determine the proper drug and dose to be used in each individual patient. | ||||||||
| 29 | 52.41 | 15389705 | 2005.02.02 | + | Lack of genetic dispositions to hyperhomocysteinemia in Alzheimer disease. | Am J Med Genet A | ||
| M Linnebank, A Linnebank, M Jeub, T Klockgether, U Wüllner, H Kölsch, R Heun, HG Koch, T Suormala, B Fowler, | ||||||||
| 30 | 52.37 | 11443539 | 2001.08.16 | + | + | Linkage and association studies of prostate cancer susceptibility: evidence for linkage at 8p22-23. | Am J Hum Genet | |
| J Xu, SL Zheng, GA Hawkins, DA Faith, B Kelly, SD Isaacs, KE Wiley, B Chang , CM Ewing, P Bujnovszky, JD Carpten, ER Bleecker, PC Walsh, JM Trent, DA Meyers, WB Isaacs, | ||||||||
| Multiple lines of evidence have implicated the short arm of chromosome 8 as harboring genes important in prostate carcinogenesis. Although most of this evidence comes from the identification of frequent somatic alterations of 8p loci in prostate cancer cells (e.g., loss of heterozygosity), studies have also suggested a role for 8p genes in mediation of inherited susceptibility to prostate cancer. To further examine this latter possibility, we performed linkage analyses, in 159 pedigrees affected by hereditary prostate cancer (HPC), using 24 markers on the short arm of chromosome 8. In the complete set of families, evidence for prostate cancer linkage was found at 8p22-23, with a peak HLOD of 1.84 (P=.004), and an estimate of the proportion of families linked (alpha) of 0.14, at D8S1130. In the 79 families with average age at diagnosis >65 years, an allele-sharing LOD score of 2.64 (P=.0005) was observed, and six markers spanning a distance of 10 cM had LOD scores >2.0. Interestingly, the small number of Ashkenazi Jewish pedigrees (n=11) analyzed in this study contributed disproportionately to this linkage. Mutation screening in HPC probands and association analyses in case subjects (a group that includes HPC probands and unrelated case subjects) and unaffected control subjects were carried out for the putative prostate cancer-susceptibility gene, PG1, previously localized to the 8p22-23 region. No statistical differences in the allele, genotype, or haplotype frequencies of the SNPs or other sequence variants in the PG1 gene were observed between case and control subjects. However, case subjects demonstrated a trend toward higher homozygous rates of less-frequent alleles in all three PG1 SNPs, and overtransmission of a PG1 variant to case subjects was observed. In summary, these results provide evidence for the existence of a prostate cancer-susceptibility gene at 8p22-23. Evaluation of the PG1 gene and other candidate genes in this area appears warranted. | ||||||||
| 31 | 52.26 | 17496163 | 2007.09.20 | + | + | Human hydroxysteroid sulfotransferase SULT2B1 pharmacogenomics: gene sequence variation and functional genomics. | J Pharmacol Exp Ther | |
| Y Ji, I Moon, J Zlatkovic, OE Salavaggione, BA Thomae, BW Eckloff, ED Wieben, DJ Schaid, RM Weinshilboum, | ||||||||
| The human hydroxysteroid sulfotransferase (SULT) 2B1 gene is a member of the cytosolic SULT gene superfamily. The two SULT2B1 isoforms, SULT2B1a and SULT2B1b, are encoded by a single gene as a result of alternative transcription initiation and alternative splicing. SULT2B1b catalyzes the sulfonation of 3beta-hydroxysteroid hormones and cholesterol, whereas SULT2B1a preferentially catalyzes pregnenolone sulfonation. We used a genotype-to-phenotype approach to identify and characterize common sequence variation in SULT2B1. Specifically, we resequenced all exons, splice junctions, and approximately 2.5 kb of the 5'-flanking regions (FRs) for each isoform using 60 DNA samples each from African-American and Caucasian-American subjects. We observed 100 polymorphisms, including four nonsynonymous coding single nucleotide polymorphisms and one 6-base pair deletion-all within the "shared" region of the open reading frame. Functional genomic studies of the wild type (WT) and five variant allozymes for each isoform performed with a mammalian expression system showed that variant allozyme activities ranged from 64 to 88% of WT for SULT2B1a and from 76 to 98% for SULT2B1b. Relative levels of immunoreactive protein were similar to those for enzyme activity. Luciferase reporter gene constructs for 2.5 kb of the SULT2B1b 5'-FR displayed a cell line-dependent pattern of variation in activity. Finally, deletion of the proline-rich SULT2B1 carboxyl terminus resulted in intracellular protein aggregate formation and accelerated degradation of the truncated protein. These studies resulted in the identification of common SULT2B1 gene sequence variation, as well as insight into the effects of that variation on the function of this important steroid-metabolizing enzyme. | ||||||||
| 32 | 52.26 | 9522436 | 1998.04.24 | + | + | Roles of two allelic variants (Arg144Cys and Ile359Leu) of cytochrome P4502C9 in the oxidation of tolbutamide and warfarin by human liver microsomes. | Xenobiotica | |
| H Yamazaki, K Inoue, T Shimada, | ||||||||
| 1. Tolbutamide methyl hydroxylation and racemic warfarin 7-hydroxylation activities were determined in liver microsomes of 39 Japanese and 45 Caucasians genotyped for the cytochrome P450 (P450 or CYP) 2C9 gene into three groups, namely the wild-type (Arg144.Ile359), and two heterozygous Cys allele (Cys144.Ile359) and Leu allele (Arg144.Leu359) variants. 2. Good correlations were found between tolbutamide methyl hydroxylation and racemic warfarin 7-hydroxylation activities in liver microsomes of Japanese and Caucasians. Humans with the Cys allele CYP2C9 variant, which was detected in 22% of Caucasians, were found to have similar catalytic rates to those of the wild-type in the oxidations of tolbutamide and racemic warfarin, whereas humans with the Leu allele, which was detected in 8% Japanese and 7% Caucasian samples, had lower catalytic rates than those of other two groups. 3. The rates of 6- and 7-hydroxylation of racemic warfarin were correlated well with those of S-warfarin, but not R-warfarin, in human liver microsomes. 4. Both human liver microsomes and recombinant CYP2C9 catalysed 7-hydroxylation of S-warfarin more extensively than those of R-warfarin. K(m)'s for the 7-hydroxylation of S-warfarin were not very different in liver microsomes of humans with these three genotypes. Anti-CYP2C9 antibodies and sulphaphenazole inhibited the 6- and 7-hydroxylation of S-warfarin, but not R-warfarin, by > 90% and the methyl hydroxylation of tolbutamide by about 50%. 5. These results suggest that humans with Leu allele of CYP2C9 have lower Vmax's for S-warfarin 7-hydroxylation and tolbutamide methyl hydroxylation than those with wild-type and Cys allele CYP2C9, although the K(m)'s are not very different in liver microsomes of these three groups of humans. R-warfarin hydroxylation may be catalysed by P450 enzymes other than CYP2C9 in man. | ||||||||
| 33 | 52.20 | 12464799 | 2003.07.07 | + | + | Identification and functional characterization of new potentially defective alleles of human CYP2C19. | Pharmacogenetics | |
| J Blaisdell, H Mohrenweiser, J Jackson, S Ferguson, S Coulter, B Chanas, T Xi, B Ghanayem, JA Goldstein, | ||||||||
| CYP2C19 is a clinically important enzyme responsible for the metabolism of a number of therapeutic drugs, such as mephenytoin, omeprazole, diazepam, proguanil, propranolol and certain antidepressants. Genetic polymorphisms in this enzyme result in poor metabolizers of these drugs. There are racial differences in the incidence of the poor metabolizer trait, which represents 13-23% of Asians but only 3-5% of Caucasians. In this study, single nucleotide polymorphisms (SNPs) in CYP2C19 were identified by direct sequencing of genomic DNA from 92 individuals from three different racial groups of varied ethnic background, including Caucasians, Asians and blacks. Several new alleles were identified containing the coding changes Arg114 His (CYP2C19*9), Pro227 Leu (CYP2C19*10), Arg150 His (CYP2C19*11), stop491 Cys (CYP2C19*12), Arg410 Cys (CYP2C19*13), Leu17 Pro (CYP2C19*14) and Ile19 Leu (CYP2C19*15). When expressed in a bacterial cDNA expression system, CYP2C19*9 exhibited a modest decrease in the V(max) for 4'-hydroxylation of -mephenytoin, and no alteration in its affinity for reductase. CYP2C19*10 exhibited a dramatically higher K(m) and lower V(max) for mephenytoin. CYP2C19*12was unstable and expressed poorly in a bacterial cDNA expression system. Clinical studies will be required to confirm whether this allele is defective in vivo. CYP2C19*9, CYP2C19*10 and CYP2C19*12 all occurred in African-Americans, or individuals of African descent, and represent new potentially defective alleles of CYP2C19 which are predicted to alter risk of these populations to clinically important drugs. | ||||||||
| 34 | 52.20 | 12642470 | 2003.10.20 | + | + | Comparative effects of thiazolidinediones on in vitro P450 enzyme induction and inhibition. | Drug Metab Dispos | |
| J Sahi, CB Black, GA Hamilton, X Zheng, S Jolley, KA Rose, D Gilbert, EL LeCluyse, MW Sinz, | ||||||||
| Rosiglitazone and pioglitazone are thiazolidinediones used for treatment of noninsulin-dependent diabetes mellitus. These compounds, along with troglitazone, were evaluated for the ability to induce cytochrome P450 enzymes (P450) in primary human hepatocyte cultures and to inhibit P450 in human microsomes. In induction studies, all three thiazolidinediones caused a dose-dependent increase in CYP3A4 activity and immunoreactive protein. While troglitazone was the most potent, rosiglitazone and pioglitazone generally exceeded troglitazone in absolute CYP3A4 activity achieved at concentrations > or =10 microM. A comparable concentration-dependent increase in CYP2B6 immunoreactive protein was observed with all three thiazolidinediones. Microarray analysis revealed rifampin > troglitazone > pioglitazone > rosiglitazone in terms of CYP3A4 mRNA induction potential with 10 microM compound. Inhibition studies conducted for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP2A6, and CYP2E1 showed troglitazone to be the most nonselective and potent inhibitor followed by rosiglitazone and pioglitazone. In vitro, the thiazolidinediones were strong inhibitors of CYP2C8, with K(i) values between 1.7 and 5.6 microM, and of CYP3A4, with K(i) values between 1.6 and 11.8 microM. Troglitazone, in addition, inhibited CYP2C9 (K(i) 0.6 microM). Although the inhibitory effects of the thiazolidinediones have not been demonstrated clinically, our results suggest there is potential for interactions with CYP2C8 substrates. This is the first report of in vitro induction of P450 enzymes by rosiglitazone and pioglitazone. While only the induction of CYP3A4 by troglitazone has been demonstrated in vivo, these results suggest that other thiazolidinediones may have the potential to cause clinically significant drug interactions at sufficiently high doses. | ||||||||
| 35 | 52.11 | 8946475 | 1997.03.14 | + | + | Genetic analysis of the human cytochrome P450 CYP2C9 locus. | Pharmacogenetics | |
| MJ Stubbins, LW Harries, G Smith, MH Tarbit, CR Wolf, | ||||||||
| Cytochrome P450 CYP2C9 metabolizes a wide variety of clinically important drugs, including phenytoin, tolbutamide, warfarin and a large number of non-steroidal anti-inflammatory drugs. Previous studies have shown that even relatively conservative changes in the amino acid composition of this enzyme can affect both its activity and substrate specificity. To date six different human CYP2C9 cDNA sequences, as well as the highly homologous CYP2C10 sequence have been reported suggesting that the CYP2C9 gene is polymorphic. Only nine single base substitutions in the coding region of CYP2C9 account for the differences seen between the CYP2C9 proteins. In this report we have developed polymerase chain reaction (PCR)-based assays to distinguish all seven sequences, and have determined their allele frequencies in the Caucasian population. Of the seven sequences studied in one hundred individuals only three appeared to be CYP2C9 alleles. These alleles termed CYP2C9*1, CYP2C9*2 and CYP2C9*3 had allele frequencies of 0.79, 0.125 and 0.085 respectively. The CYP2C10 gene could not be found in any of the samples studied. The assays developed here will allow the prediction of CYP2C9 phenotype, thus identifying those individuals who may exhibit different drug pharmacokinetics for CYP2C9 substrates. | ||||||||
| 36 | 51.95 | 8000304 | 1995.01.25 | + | + | Analysis of cytochrome P450 2E1 genetic polymorphisms in relation to human lung cancer. | Cancer Epidemiol Biomarkers Prev | |
| S Kato, PG Shields, NE Caporaso, H Sugimura, GE Trivers, MA Tucker, BF Trump, A Weston, CC Harris, | ||||||||
| Human cancer risk assessment using molecular genetic techniques is a rapidly emerging field. Many studies suggest that both inherited and acquired genetic predispositions play an important role in carcinogenesis. Cytochrome P450 (CYP) 2E1 is involved in the metabolic activation of N-nitrosamines and other low molecular weight compounds. A recently described genetic polymorphism of CYP2E1 [DraI restriction fragment length polymorphism (RFLP)] has been associated with an increased risk of lung cancer in Japanese. We have assessed the allelic frequency of three RFLPs (PstI, RsaI, and DraI) in African-Americans (n = 109), Caucasian Americans (n = 153), and octogenarian Japanese (n = 42), and also in a United States case-control study of lung cancer (histologically confirmed lung cancer, n = 58; controls, n = 56; total, n = 114). The relationship of the CYP2E1 DraI polymorphism to other CYP2E1 polymorphisms (PstI and RsaI RFLP) was examined. The allelic frequency of the DraI C minor allele for all subjects was 0.09 in Caucasians, 0.09 in African-Americans, and 0.31 in Japanese. In the case-control study of lung cancer, no association of the CYP2E1 DraI genotype with lung cancer was found (odds ratio, 1.57; 95% confidence interval, 0.59-4.18). Comparison after discordant CYP2E1 genotypes suggests the presence of different haplotypes in Americans and Japanese. These results indicate that the CYP2E1 DraI RFLP is probably not a cancer risk factor in United States Caucasian or African-Americans, although statistical power is limited given the low frequency of the CYP2E1 DraI C minor alleles. | ||||||||
| 37 | 51.94 | 15592323 | 2005.01.14 | + | + | A novel polymorphism of human CYP2A6 gene CYP2A6*17 has an amino acid substitution (V365M) that decreases enzymatic activity in vitro and in vivo. | Clin Pharmacol Ther | |
| T Fukami, M Nakajima, R Yoshida, Y Tsuchiya, Y Fujiki, M Katoh, HL McLeod, T Yokoi, | ||||||||
| Cytochrome P450 (CYP) 2A6 is a major CYP responsible for the metabolism of nicotine and coumarin in humans. We identified a novel allele, designated CYP2A6*17 , which contains A51G (exon 1), C209T (intron 1), G1779A (exon 3), C4489T (intron 6), G5065A (V365M, exon 7), G5163A (intron 7), C5717T (exon 8), and A5825G (intron 8). We developed a genotyping method by polymerase chain reaction-restriction fragment length polymorphism for the CYP2A6*17 allele, targeting the G5065A mutation. The allele frequency in black subjects (n = 96) was 9.4% (95% confidence interval [CI], 5.3%-13.5%). The allele was not found in white subjects (95% CI, 0%-0.9%; n = 163), Japanese subjects (95% CI, 0%-1.6%; n = 92), and Korean subjects (95% CI, 0%-0.7%; n = 209). To examine the effects of the amino acid change in the CYP2A6*17 allele on the enzymatic activity, we expressed a wild-type or variant (V365M) CYP2A6 together with NADPH-CYP reductase in Escherichia coli . For coumarin 7-hydroxylation, the apparent Michaelis-Menten constant value of variant CYP2A6 (1.06 +/- 0.11 micromol/L) was significantly (P < .005) higher than that of wild type (0.60 +/- 0.05 micromol/L). The maximum velocity values of the wild-type and variant CYP2A6 were 0.61 +/- 0.06 and 0.64 +/- 0.07 pmol . min -1 . pmol -1 CYP, respectively. For nicotine C -oxidation, the apparent Michaelis-Menten constant values of the wild-type or variant CYP2A6 were 31.6 +/- 2.9 micromol/L and 31.3 +/- 3.1 micromol/L, respectively. The maximum velocity value of variant CYP2A6 (0.72 +/- 0.21 pmol . min -1 . pmol -1 CYP) was significantly (P < .05) lower than that of the wild type (1.80 +/- 0.42 pmol . min -1 . pmol -1 CYP). Thus the intrinsic clearance values for coumarin 7-hydroxylation and nicotine C -oxidation by the variant were both significantly (P < .05) decreased to 40% to 60% compared with the wild type. Furthermore, cotinine/nicotine ratios after 1 piece of nicotine gum was chewed, used as an index of in vivo nicotine metabolism, were significantly (P < .05) decreased in heterozygotes of the CYP2A6*17 allele (5.4 +/- 2.7, n = 12) compared with homozygotes of the wild type (11.5 +/- 10.5, n = 37). A subject with CYP2A6*17 / CYP2A6*17 revealed the lowest cotinine/nicotine ratio (1.8). We found a novel allele in black subjects that affects the nicotine metabolism in vitro and in vivo. | ||||||||
| 38 | 51.91 | 8747409 | 1996.10.24 | + | + | An efficient strategy for detection of known and new mutations of the CYP2D6 gene using single strand conformation polymorphism analysis. | Pharmacogenetics | |
| F Broly, D Marez, N Sabbagh, M Legrand, S Millecamps, JM Lo Guidice, P Boone, UA Meyer, | ||||||||
| To detect mutations in the cytochrome P450 CYP2D6 gene (CYP2D6), we developed a strategy based on single-strand conformation polymorphism (SSCP) analysis of the gene amplified by polymerase chain reaction (PCR). The efficiency of the method was evaluated by analysing DNA samples from extensive metabolizers (EM) and poor metabolizers (PM) of debrisoquine. Haplotypes, alleles and mutations of CYP2D6 had previously been characterized in each individual using PCR assays, Xba I restriction fragment length polymorphism (RFLP) and sequencing. PCR-SSCP results were in complete agreement with those obtained using established methods. All previously characterized mutations were associated with particular shifts in the electrophoretic mobility of DNA fragments allowing their identification. We further tested the efficiency of PCR-SSCP for detecting new CYP2D6 mutations. DNA from a PM subject presumed to carry an unknown non-functional mutant allele of CYP2D6 was amplified and bands with aberrant migration patterns were observed on SSCP gels. Sequence analysis of the corresponding DNA fragments revealed the causative mutations. In this way, a novel non-functional allele of the gene, carrying three previously reported mutations and a new mutation in the third exon which results in a premature termination codon, was characterized. Finally, CYP2D6 SSCP analysis was performed on DNA amplified with fluorescent primers and an automated DNA sequencer was used for SSCP analysis of products. We conclude that the PCR-SSCP approach is a powerful method of identifying simultaneously known and new mutations of the CYP2D6 gene. | ||||||||
| 39 | 51.90 | 9170147 | 1997.07.29 | + | + | Relationship between CYP2C9 and 2C19 genotypes and tolbutamide methyl hydroxylation and S-mephenytoin 4'-hydroxylation activities in livers of Japanese and Caucasian populations. | Pharmacogenetics | |
| K Inoue, H Yamazaki, K Imiya, S Akasaka, FP Guengerich, T Shimada, | ||||||||
| Genomic DNA was isolated from livers of 39 Japanese and 45 Caucasians and the genotypes of CYP2C9 and 2C19 genes were determined with PCR methods using synthetic oligonucleotide primers. Liver microsomes were also prepared from these human samples and activities for tolbutamide methyl hydroxylation and S-mephenytoin 4'-hydroxylation were determined. The single base mutation of C416T (Arg144Cys) in CYP2C9 was detected in 22% of Caucasians but not in Japanese samples. Another single base mutation at A1061C (Ile359Leu) in the CYP2C9 gene was found with frequencies of about 8% in both races. We did not detect any individuals who have either homozygous Cys144/Cys144 or Leu359/Leu359 CYP2C9 variant nor both heterozygous Cys144-Ile359 and Arg144-Leu359 CYP2C9 variant in the human samples examined. The CYP2C19m2 genetic polymorphism was found only in Japanese people, while CYP2C19m1 type was determined in both races, with higher incidence in Japanese than in Caucasian population. Immunoblotting analysis of human liver microsomes suggested that CYP2C9 is a major component of the human CYP2C enzyme pool; it accounted for approximately 20% of total P450 in liver microsomes of both human populations. The levels of CYP2C19 protein were determined to be about 0.8% and 1.4% of total P450 (mean) in Japanese and Caucasians, respectively. We did not detect CYP2C19 protein in liver microsomes of humans who were genotyped for CYP2C19 gene as m1/m1, m1/m2, and m2/m2 variants but detected CYP2C9 protein in all of the samples examined. Good correlations were found between levels of CYP2C9 and activities of tolbutamide methyl hydroxylation (r = 0.77) and between levels of CYP2C19 and activities of S-mephenytoin 4'-hydroxylation (r = 0.86) in liver microsomes of the human samples examined. Tolbutamide methyl hydroxylation activities were lower in human samples with the Leu359 allele of CYP2C9 than those with the Cys144 allele and wild-type (Arg144-Ile359); the former type showed slightly higher K(m) values. When calculated on P450 basis, liver microsomes of individuals having m1/m1, m1/m2, and m2/m2 types of CYP2C19 had very low catalytic activities for S-mephenytoin 4'-hydroxylation. These results provide useful comparisons for pharmacokinetic and toxicokinetic models of some of the clinically used drugs that are oxidized by CYP2C proteins in humans. | ||||||||
| 40 | 51.80 | 7773301 | 1995.07.12 | + | + | Detection of CYP2C9 polymorphism based on the polymerase chain reaction in Chinese. | Pharmacogenetics | |
| SL Wang, J Huang, MD Lai, JJ Tsai, | ||||||||
| Cytochrome P450 (CYP) 2C9 catalyses the metabolism of a wide range of drugs. Previous studies have shown the differences in the amino acid composition among CYP2C9 variants at Cys144/Arg, Tyr358/Cys, Leu359/Ile, and Gly417/Asp. PCR-endonuclease digestion methods have been developed to detect these four possible polymorphisms. The T416-->C mutation in exon 3 of CYP2C9 (Cys144-->Arg) creates an Ava II site. In the 135 subjects we tested, all leukocyte DNA samples showed a complete Ava II digestion indicating homozygous C416 (Arg144). A Tyr358-->Cys mutation will create a Nsi I site at codon 1057-1063 in exon 7. In 40 subjects tested, all samples showed negative results. DNA sequencing on a few samples showed Tyr358Ile359. A mismatched PCR primer pair was then designed to detect codon C1061-->A (Leu359-->Ile) mutation. In 115 subjects tested, 111 samples showed a complete Nsi I digestion (Ile359) and four samples showed heterozygous results. Another mismatched PCR primer pair was used to confirm the C1061 codon in heterozygous subjects. The four heterozygous subjects showed partial digestion with endonuclease Kpn I, which confirmed the heterozygous Ile/Leu at amino acid 359. The G1236-->A mutation in exon 8 of CYP2C9 (Gly417-->Asp) creates a Hph I site. In all 46 subjects, homozygous G1236 (Gly417) was found. Most Chinese subjects actually have Arg144 Tyr358 Ile359 Gly417 in CYP2C9 as previously reported human-2. Furthermore, we found an A-->T (+12 position in intron 2) mutation in our CYP2C9 sequencing process. The mutation creates a NIa III site.(ABSTRACT TRUNCATED AT 250 WORDS) | ||||||||
| 41 | 51.79 | 1688241 | 1993.05.28 | + | + | Genetic and metabolic criteria for the assignment of debrisoquine 4-hydroxylation (cytochrome P4502D6) phenotypes. | Pharmacogenetics | |
| AK Daly, M Armstrong, SC Monkman, ME Idle, JR Idle, | ||||||||
| A randomly selected population of 73 volunteers, together with 22 previously established poor metabolisers of debrisoquine, were phenotyped for their ability to 4-hydroxylate debrisoquine and were also analysed for a number of mutations in the CYP2D6 gene. Genotyping was performed using both restriction fragment length polymorphism with the restriction enzyme Xba I, together with two separate polymerase chain reaction assays. Together, these assays detected 98% of mutant alleles in the poor metaboliser group which corresponded to positive identification of 95% of this group. The most common mutant allele detected as the 29B which comprised 75% of total alleles in the poor metaboliser group, whereas the 29A had a frequency of 0.11. Two other allelic variants, which were detectable by restriction fragment length polymorphism analysis occurred at frequencies of 0.07 and 0.05. In the volunteer group, 2.7% of subjects were genotypically poor metabolisers, 35.6% heterozygous extensive metabolisers and 61.7% homozygous extensive metabolisers, on the basis of the genotyping assays used. A good correlation between debrisoquine metabolic ratio and genotype was obtained particularly for subjects genotyped as homozygous extensive metabolisers. | ||||||||
| 42 | 51.77 | 12208565 | 2002.11.22 | + | + | No association between the serotonergic polymorphisms and incidence of nausea induced by fluvoxamine treatment. | Eur Neuropsychopharmacol | |
| H Takahashi, K Yoshida, K Ito, K Sato, M Kamata, H Higuchi, T Shimizu, K Ito, K Inoue, T Tezuka, T Suzuki, T Ohkubo, K Sugawara, | ||||||||
| We investigated the association between serotonergic polymorphisms and incidence of nausea, which is the most frequent side-effect of selective serotonin reuptake inhibiters (SSRIs), in 66 patients treated with fluvoxamine in a protocolized-dosing method. We focused on three polymorphisms of serotonin (5-HT) neuronal systems such as 5-HT transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR), a variable number of tandem repeat (VNTR) polymorphism in the second intron of the 5-HTT gene (STin2) and tryptophan hydroxylase (TPH) gene polymorphism in intron 7 (TPH-A218C), which have been reported to possess positive association with treatment response to SSRIs. In addition to this, the relationship between development of nausea and treatment response was also analyzed. Results suggested that these three polymorphisms did not affect the development of fluvoxamine-induced nausea, and that incidence of nausea was not a phenomenon that predicts the treatment response to fluvoxamine. | ||||||||
| 43 | 51.66 | 15746444 | 2005.09.22 | + | + | Common variants in myocardial ion channel genes modify the QT interval in the general population: results from the KORA study. | Circ Res | |
| A Pfeufer, S Jalilzadeh, S Perz, JC Mueller, M Hinterseer, T Illig, M Akyol, C Huth, A Schöpfer-Wendels, B Kuch, G Steinbeck, R Holle, M Näbauer, HE Wichmann, T Meitinger, S Kääb, | ||||||||
| Altered myocardial repolarization is one of the important substrates of ventricular tachycardia and fibrillation. The influence of rare gene variants on repolarization is evident in familial long QT syndrome. To investigate the influence of common gene variants on the QT interval we performed a linkage disequilibrium based SNP association study of four candidate genes. Using a two-step design we analyzed 174 SNPs from the KCNQ1, KCNH2, KCNE1, and KCNE2 genes in 689 individuals from the population-based KORA study and 14 SNPs with results suggestive of association in a confirmatory sample of 3277 individuals from the same survey. We detected association to a gene variant in intron 1 of the KCNQ1 gene (rs757092, +1.7 ms/allele, P=0.0002) and observed weaker association to a variant upstream of the KCNE1 gene (rs727957, +1.2 ms/allele, P=0.0051). In addition we detected association to two SNPs in the KCNH2 gene, the previously described K897T variant (rs1805123, -1.9 ms/allele, P=0.0006) and a gene variant that tags a different haplotype in the same block (rs3815459, +1.7 ms/allele, P=0.0004). The analysis of additive effects by an allelic score explained a 10.5 ms difference in corrected QT interval length between extreme score groups and 0.951 of trait variance (P<0.00005). These results confirm previous heritability studies indicating that repolarization is a complex trait with a significant heritable component and demonstrate that high-resolution SNP-mapping in large population samples can detect and fine map quantitative trait loci even if locus specific heritabilities are small. | ||||||||
| 44 | 51.66 | 10739168 | 2000.05.17 | + | + | Variation in induced CYP1A1 levels: relationship to CYP1A1, Ah receptor and GSTM1 polymorphisms. | Pharmacogenetics | |
| J Smart, AK Daly, | ||||||||
| The genotypic basis of interindividual variation in levels of induced CYP1A1 activity has been investigated by screening both the CYP1A1 gene and the Ah receptor gene (AhR) for both previously described and novel polymorphisms. A 103-fold level of interindividual variation in induced CYPlA1 activity [ethoxyresorufin O-deethylase (EROD)] was observed in lymphocytes from a group of 30 Caucasian volunteers. High levels of induced EROD activity did not correlate with the presence of CYP1A1*2 or CYP1A1*4 alleles or with the GSTM1 null genotype. Novel CYP1A1 alleles with the base substitutions C4151T, G-469A and C-459T respectively, were detected by screening the coding exons and approximately 1 kb of upstream sequence in 20 individuals by single-strand conformational polymorphism (SSCP) analysis but none of the three novel alleles appeared to be associated with high induced CYP1A1 activity in the study group. Screening of the 11 exons of the AhR gene by SSCP analysis confirmed the existence of the previously described G1721A polymorphism in a Caucasian population and a novel allele (G1768A which results in the amino acid substitution V5701) was also detected. The novel allele was very rare in Caucasians though more common in African-Americans. Individuals with at least one copy of the G1721A AhR variant allele showed a significantly higher level of induced CYP1A1 activity compared with individuals negative for the polymorphism (P = 0.0001). A similar finding was obtained for induced CYP1A1 protein levels determined by immunoblotting. Levels of induced CYP1A1 activity were also found to show a sex difference with women showing a significantly lower induced activity compared with men. We conclude that genotypes for the G1721A AhR polymorphism and gender appear to be determinants of levels of induced CYP1A1 activity and that interindividual variation in levels of induced CYP1A1 activity appears to be associated more with regulatory factors than polymorphism in the CYP1A1 gene. | ||||||||
| 45 | 51.43 | 12811365 | 2003.07.02 | + | + | Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. | Clin Pharmacol Ther | |
| Y Nishizato, I Ieiri, H Suzuki, M Kimura, K Kawabata, T Hirota, H Takane, S Irie, H Kusuhara, Y Urasaki, A Urae, S Higuchi, K Otsubo, Y Sugiyama, | ||||||||
| OBJECTIVE: Our objective was to quantitate the contribution of the genetic polymorphisms of the genes for 2 human organic anion transporters-organic anion transporting polypeptide C (OATP-C) and organic anion transporter 3 (OAT3)-to the pharmacokinetics of pravastatin. METHODS: Genetic polymorphisms were screened by polymerase chain reaction-single-strand conformation polymorphism analysis, after sequencing with deoxyribonucleic acid obtained from 120 healthy volunteers. To examine whether polymorphisms in these 2 genes of interest alter transport activity, we conducted a clinical study (n = 23) with pravastatin as a selective probe drug. RESULTS: Among 120 healthy individuals, 5 nonsynonymous variants and 1 nonsynonymous variant were observed in the OATP-C and OAT3 genes, respectively. The polymorphisms in the OAT3 gene did not appear to be associated with changes in renal and tubular secretory clearance. In contrast, the OATP-C variants were associated with differences in the disposition kinetics of pravastatin. Subjects with the OATP-C*15 allele (Asp130Ala174) had a reduced total and nonrenal clearance, as compared with those with the OATP-C*1b allele (Asp130Val174); nonrenal clearance values in *1b/*1b (n = 4), *1b/*15 (n = 9), and *15/*15 (n = 1) subjects were 2.01 +/- 0.42 L. kg(-1). h(-1), 1.11 +/- 0.34 L. kg(-1). h(-1), and 0.29 L. kg(-1). h(-1), respectively, and the difference between *1b/*1b and *1b/*15 subjects was significant (P <.05). CONCLUSION: Certain commonly occurring single-nucleotide polymorphisms in OATP-C, such as T521C (Val174Ala), are likely to be associated with altered pharmacokinetics of pravastatin. Large clinical studies are needed to confirm these observations. | ||||||||
| 46 | 51.32 | 15087453 | 2004.08.11 | + | + | DNA methyltransferase 1 knock down induces gene expression by a mechanism independent of DNA methylation and histone deacetylation. | J Biol Chem | |
| S Milutinovic, SE Brown, Q Zhuang, M Szyf, | ||||||||
| DNA methyltransferase 1 (DNMT1) catalyzes the post-replication methylation of DNA and is responsible for maintaining the DNA methylation pattern during cell division. A long list of data supports a role for DNMT1 in cellular transformation and inhibitors of DNMT1 were shown to have antitumorigenic effects. It was long believed that DNMT1 promoted tumorigenesis by maintaining the hypermethylated and silenced state of tumor suppressor genes. We have previously shown that DNMT1 knock down by either antisense oligonucleotides directed at DNMT1 or expressed antisense activates a number of genes involved in stress response and cell cycle arrest by a DNA methylation-independent mechanism. In this report we demonstrate that antisense knock down of DNMT1 in human lung carcinoma A549 and embryonal kidney HEK293 cells induces gene expression by a mechanism that does not involve either of the known epigenomic mechanisms, DNA methylation, histone acetylation, or histone methylation. The mechanism of activation of the cell cycle inhibitor p21 and apoptosis inducer BIK by DNMT1 inhibition is independent of the mechanism of activation of the same genes by histone deacetylase inhibition. We determine whether DNMT1 knock down activates one of the nodal transcription activation pathways in the cell and demonstrate that DNMT1 activates Sp1 response elements. This activation of Sp1 response does not involve an increase in either Sp1 or Sp3 protein levels in the cell or the occupancy of the Sp1 elements with these proteins. The methylation-independent regulation of Sp1 elements by DNMT1 unravels a novel function for DNMT1 in gene regulation. DNA methylation was believed to be a mechanism for suppression of CG-rich Sp1-bearing promoters. Our data suggest a fundamentally different and surprising role for DNMT1 regulation of CG-rich genes by a mechanism independent of DNA methylation and histone acetylation. The implications of our data on the biological roles of DNMT1 and the therapeutic potential of DNMT1 inhibitors as anticancer agents are discussed. | ||||||||
| 47 | 51.04 | 15578613 | 2005.03.14 | + | + | Quantitative trait locus analysis of candidate gene alleles associated with attention deficit hyperactivity disorder (ADHD) in five genes: DRD4, DAT1, DRD5, SNAP-25, and 5HT1B. | Am J Med Genet B Neuropsychiatr Genet | |
| J Mill, X Xu, A Ronald, S Curran, T Price, J Knight, I Craig, P Sham, R Plomin, P Asherson, | ||||||||
| It has been widely postulated that the categorical diagnosis of attention deficit hyperactivity disorder (ADHD) should be seen as the extreme end of a set of traits quantitatively distributed in the general population. A consequence of this is that the genes associated with DSM-IV ADHD should also influence these underlying traits in non-affected individuals. The aim of this study was to examine if specific candidate loci previously shown to be associated with DSM-IV ADHD, also act as quantitative trait loci (QTLs) for ADHD-symptoms in the general population. We have genotyped five candidate markers in a population-based sample of male dizygous twin-pairs (n = 329 pairs). We found little evidence to support a role for the previously-nominated alleles of a DRD4 VNTR, a 5HT1B SNP, or a microsatellite marker near to DRD5, in the distribution of ADHD-symptoms scores; however, we found some evidence to suggest that the DAT1 3'UTR VNTR and weak evidence that a microsatellite in SNAP-25 may have a role in continuous measures of ADHD-symptoms hyperactivity above and beyond their role in clinical ADHD. | ||||||||
| 48 | 50.94 | 16166573 | 2006.01.12 | + | + | Association of phosphodiesterase 4D gene with ischemic stroke in a Pakistani population. | Stroke | |
| D Saleheen, S Bukhari, SR Haider, A Nazir, S Khanum, S Shafqat, MK Anis, P Frossard, | ||||||||
| BACKGROUND AND OBJECTIVES: Identification of STRK1 locus by the deCODE group followed by the discovery of phosphodiesterase 4D (PDE4D) gene in strong association with ischemic stroke patients has provided useful insights toward understanding the genetic etiology of the disease. In this study, we aimed at investigating the association between 3 polymorphisms of the PDE4D gene and ischemic stroke in the Pakistani population. METHODS: Three polymorphisms in PDE4D gene were analyzed in 200 patients of ischemic stroke and 250 controls of Pakistani origin using polymerase chain reaction-restriction fragment length polymorphism method. Data were coded and entered in SPSS Windows (version 12.0). Odds ratios and 95% CIs were calculated using multivariate logistic regression analysis. RESULTS: Marker SNP83(rs966221) was found significantly associated with ischemic stroke on univariate and multivariate analysis (P<0.005; odds ratio, 1.64 [1.13 to 2.40]). Haplotype analysis for markers in linkage disequilibrium failed to show any association with the disease. CONCLUSIONS: The association of PDE4D variation with ischemic stroke extends to the Pakistani population and supports a role for phosphodiesterases in stroke pathogenesis. | ||||||||
| 49 | 50.92 | 12496052 | 2003.04.04 | + | + | 5,10-Methylenetetrahydrofolate reductase codon 677 and 1298 polymorphisms and colon cancer in African Americans and whites. | Cancer Epidemiol Biomarkers Prev | |
| T Keku, R Millikan, K Worley, S Winkel, A Eaton, L Biscocho, C Martin, R Sandler, | ||||||||
| We evaluated polymorphisms in methylenetetrahydrofolate reductase (MTHFR), folate intake and alcohol consumption in relation to risk of colon cancer in a population-based case-control study in North Carolina. The study included 555 cases (244 African Americans and 311 whites) and 875 controls (331 African Americans and 544 whites). Total folate intake of <400 versus > or =400 microg/day showed a weak positive association with colon cancer among both African Americans [adjusted odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.0-2.0] and whites (OR = 1.6, 95% CI = 1.2-2.2). No association was observed with use of alcohol. Compared with wild-type genotypes, there was no association between the low activity MTHFR codon 677 TT genotype and colon cancer, but the low activity codon 1298 CC genotype was inversely associated with colon cancer in whites (OR = 0.5, 95% CI = 0.3-0.9). Unlike previous studies, we did not observe a strong protective effect of the codon 677 TT low-activity genotype when folate intake was high. Instead, we observed an increased risk of colon cancer when folate intake was low for participants with wild- type genotypes. Adjusted ORs for the combined effects of codon 677 CC and codon 1298 AA genotypes and folate intake <400 microg/day were 1.9 (95% CI = 1.1-3.4) in African Americans and 2.5 (95% CI = 1.2-5.2) in whites. Our results suggest that variation at MTHFR codon 1298 (within the COOH-terminal region) may be more important for colon cancer than variation at codon 677 (NH(2)-terminal region), and in populations where folate intake is low, wild-type MTHFR activity may increase risk for colon cancer. | ||||||||
| 50 | 50.80 | 10899164 | 2000.11.13 | + | + | Clustering of mutations in the first transmembrane domain of the human reduced folate carrier in GW1843U89-resistant leukemia cells with impaired antifolate transport and augmented folate uptake. | J Biol Chem | |
| S Drori, G Jansen, R Mauritz, GJ Peters, YG Assaraf, | ||||||||
| We have studied the molecular basis for the resistance of human CEM leukemia cells to GW1843, a thymidylate synthase inhibitor. GW1843-resistant cells displayed a approximately 100-fold resistance to GW1843 and methotrexate but were collaterally sensitive to the lipophilic antifolates trimetrexate and AG337, which enter cells by diffusion. These cells exhibited a 12-fold decreased methotrexate influx but surprisingly had a 2-fold decreased folic acid growth requirement. This was associated with a 4-fold increased influx of folic acid, a 3.5-fold increased steady-state level of folic acid, and a 2.3-fold expansion of the cellular folate pool. Characterization of the transport kinetic properties revealed that GW1843-resistant cells had the following alterations: (a) 11-fold decreased transport K(m) for folic acid; (b) 6-fold increased transport K(m) for GW1843; and (c) a slightly increased transport V(max) for folic acid. Sequence analysis showed that GW1843-resistant cells contained the mutations Val-29 --> Leu, Glu-45 --> Lys, and Ser-46 --> Ile in the first transmembrane domain of the reduced folate carrier. Transfection of the mutant-reduced folate carrier cDNA into methotrexate transport null cells conferred resistance to GW1843. This is the first demonstration of multiple mutations in a confined region of the human reduced folate carrier in an antifolate-resistant mutant. We conclude that certain amino acid residues in the first transmembrane domain play a key role in (anti)folate binding and in the conferring of drug resistance. | ||||||||
| 51 | 50.76 | 12771034 | 2003.07.10 | + | + | A specific haplotype of single nucleotide polymorphisms on chromosome 19q13.2-3 encompassing the gene RAI is indicative of post-menopausal breast cancer before age 55. | Carcinogenesis | |
| BA Nexø, U Vogel, A Olsen, T Ketelsen, Z Bukowy, BL Thomsen, H Wallin, K Overvad, A Tjønneland, | ||||||||
| The new genetic information, in particular the greatly increased density of markers in the chromosomal maps, may permit analysis of the importance of genes in the development of disease exclusively from molecular epidemiological studies. Motivated by our previous results on the same region in relation to basal cell carcinoma we have investigated the occurrence of post-menopausal breast cancer in relation to a number of single nucleotide polymorphisms in the chromosomal region 19q13.2-3. A case-control study including 425 human cases and a similar number of controls was nested in a population-based prospective investigation encompassing 24 697 Danish post-menopausal women (aged 50-64 at inclusion) living in Copenhagen or Aarhus. We combined three markers located together in or near the gene RAI into a high-risk haplotype. Compared with all other haplotypes, those who were homozygous had a rate ratio of 1.64 (95% CI 1.17-2.29, P < or = 0.004) for development of breast cancer. When we further focused on those persons with post-menopausal breast cancer before age 55 the rate ratio increased to 9.5 (95% CI 2.21-40.79, P < or = 0.003). The likely explanation for our results is a common recessive genetic variant located in or near the gene RAI, which, when homozygous, conveys an increased risk of breast cancer. Presumably it is identical to the genetic variant previously observed in the same region that increases the risk of basal cell carcinoma before age 50. | ||||||||
| 52 | 50.72 | 17010193 | 2006.11.08 | + | + | Mutation analysis and characterization of ATR sequence variants in breast cancer cases from high-risk French Canadian breast/ovarian cancer families. | BMC Cancer | |
| F Durocher, Y Labrie, P Soucy, O Sinilnikova, D Labuda, P Bessette, J Chiquette, R Laframboise, J Lépine, B Lespérance, G Ouellette, R Pichette, M Plante, SV Tavtigian, J Simard, | ||||||||
| BACKGROUND: Ataxia telangiectasia-mutated and Rad3-related (ATR) is a member of the PIK-related family which plays, along with ATM, a central role in cell-cycle regulation. ATR has been shown to phosphorylate several tumor suppressors like BRCA1, CHEK1 and TP53. ATR appears as a good candidate breast cancer susceptibility gene and the current study was designed to screen for ATR germline mutations potentially involved in breast cancer predisposition. METHODS: ATR direct sequencing was performed using a fluorescent method while widely available programs were used for linkage disequilibrium (LD), haplotype analyses, and tagging SNP (tSNP) identification. Expression analyses were carried out using real-time PCR. RESULTS: The complete sequence of all exons and flanking intronic sequences were analyzed in DNA samples from 54 individuals affected with breast cancer from non-BRCA1/2 high-risk French Canadian breast/ovarian families. Although no germline mutation has been identified in the coding region, we identified 41 sequence variants, including 16 coding variants, 3 of which are not reported in public databases. SNP haplotypes were established and tSNPs were identified in 73 healthy unrelated French Canadians, providing a valuable tool for further association studies involving the ATR gene, using large cohorts. Our analyses led to the identification of two novel alternative splice transcripts. In contrast to the transcript generated by an alternative splicing site in the intron 41, the one resulting from a deletion of 121 nucleotides in exon 33 is widely expressed, at significant but relatively low levels, in both normal and tumoral cells including normal breast and ovarian tissue. CONCLUSION: Although no deleterious mutations were identified in the ATR gene, the current study provides an haplotype analysis of the ATR gene polymorphisms, which allowed the identification of a set of SNPs that could be used as tSNPs for large-scale association studies. In addition, our study led to the characterization of a novel Delta33 splice form, which could generate a putative truncated protein lacking several functional domains. Additional studies in large cohorts and other populations will be needed to further evaluate if common and/or rare ATR sequence variants can be associated with a modest or intermediate breast cancer risk. | ||||||||
| 53 | 50.58 | 17289397 | 2007.08.29 | + | + | Tolerability of statins is not linked to CYP450 polymorphisms, but reduced CYP2D6 metabolism improves cholesteraemic response to simvastatin and fluvastatin. | Pharmacol Res | |
| P Zuccaro, G Mombelli, L Calabresi, D Baldassarre, I Palmi, CR Sirtori, | ||||||||
| Statin therapy, although generally well tolerated, leads not infrequently to significant subjective and at times objective adverse effects (AEs), mainly of a muscular nature. The genetic background of these AEs is not clear and possibly side effects and lipid lowering efficacy may be linked. Aim of the study was a detailed evaluation of CYP450 and apolipoprotein E gene polymorphisms in two large series of age-sex matched patients with and without muscular side effects to statins. In a Clinical Institution specialised in lipid-lipoprotein disorders, 50 statin treated patients were selected, with subjective or objective statin-associated myopathy, evaluated using standardized forms. These were sex and age matched with 50 statin-treated patients from the same Clinic, without any subjective or objective complaints. DNA samples for the evaluation of CYP450 genetic polymorphisms and apo E genotypes were collected in order to assess correlations with both genetic polymorphisms and AEs, as well as with therapeutic efficacy. None of the assessed CYP450 polymorphisms appeared to be related to an increased incidence of AEs. The CYP2D6 *1/*4 and *4/4* poor metabolizer (PM) status was associated to a higher efficacy of statins metabolized by this system and, in addition, the apo E2 genotype was, in this series, linked to increased HDL-C levels after therapy. Patients with statin associated myopathy are not characterized by significantly different genotypes for the CYP450s responsible for statin metabolism. On the other hand, CYP2D6 PM status is associated to an increased efficacy of statins metabolized by this system. | ||||||||
| 54 | 50.54 | 8097947 | 1993.06.10 | + | + | PCR-based CYP2D6 genotyping for Finnish lung cancer patients. | Pharmacogenetics | |
| A Hirvonen, K Husgafvel-Pursiainen, S Anttila, A Karjalainen, O Pelkonen, H Vainio, | ||||||||
| Polymorphism of the gene encoding for debrisoquine hydroxylase, i.e. CYP2D6, was determined genotypically for 122 healthy controls and 106 lung cancer patients using Xba I restriction fragment length polymorphism (RFLP) analysis, together with a combination of two recently published polymerase chain reaction (PCR) based approaches. Three different mutated alleles of the CYP2D6 gene were detected; CYP2D6B comprised 11.1% and 10.4% of the total alleles in the controls and in the lung cancer patients, CYP2D6A had frequencies of 5.7% and 2.8%, and CYP2D6D had frequencies of 3.3% and 2.4%, respectively. Only 17 of the 24 44 kb Xba I alleles (71%) were confirmed as defective alleles carrying the mutation in CYP2D6B loci, whereas all four 15 + 9 kb Xba I alleles contained the CYP2D6B mutation. Out of the 122 healthy controls, seven subjects (5.7%) were detected as poor metabolizers (PMs) of debrisoquine by the presence of two defective alleles, whereas only one PM genotype was found in the lung cancer patient group (0.9%). The reliability of this analysis was confirmed in a subgroup of the control subjects phenotyped by debrisoquine, where a perfect correlation between CYP2D6 phenotype and genotype was obtained. We observed no significant difference in the allelic frequencies between lung cancer patients with a history of heavy smoking and those who smoked less. However, statistical analysis showed a significant difference (p = 0.05) in distribution of the PM-associated genotypes between lung cancer patients (1/106) and healthy controls (7/122). This data thus supports the hypothesis that there is an increased risk of lung cancer for individuals who are extensive metabolizers of debrisoquine. | ||||||||
| 55 | 50.49 | 11434512 | 2001.12.14 | + | + | Effects of genotypic differences in CYP2C19 status on cure rates for Helicobacter pylori infection by dual therapy with rabeprazole plus amoxicillin. | Pharmacogenetics | |
| T Furuta, N Shirai, M Takashima, F Xiao, H Hanai, K Nakagawa, H Sugimura, K Ohashi, T Ishizaki, | ||||||||
| Rabeprazole is a potent proton pump inhibitor and is mainly reduced to thioether rabeprazole by a non-enzymatic pathway and partially metabolized to demethylated rabeprazole by CYP2C19 in the liver. We intended to determine a cure rate for Helicobacter pylori infection by dual rabeprazole/amoxicillin therapy in relation to CYP2C19 genotype status prospectively. Ninety-seven patients with gastritis and H. pylori infection completed the dual therapy with 10 mg of rabeprazole bid and 500 mg of amoxicillin tid for 2 weeks. At 1 month after treatment, cure of H. pylori infection was assessed on the basis of histology, a rapid urease test, culture, polymerase chain reaction (PCR), and 13C-urea breath test. CYP2C19 genotype status was determined by a PCR-restriction fragment length polymorphism method. Of the 97 patients, 33 were homozygous extensive metabolizers (homEM), 48 were heterozygous extensive metabolizers (hetEM), and 16 were poor metabolizers (PM). Cure of H. pylori infection was achieved in 79 of the 97 patients (81.4%, 95%CI = 71.9-88.7). Significant differences in cure rates among the homEM, hetEM, and PM groups were observed; 60.6% (95%CI = 42.1-77.3), 91.7% (95%CI = 80.0-97.7), and 93.8% (95%CI = 69.8-99.8), respectively (P = 0.0007). Twelve patients without cure after initial treatment (10 homEMs and 2 hetEMs) were successfully retreated with rabeprazole 10 mg q.i.d. and amoxicillin 500 mg q.i.d. for 2 weeks. The cure rates for H. pylori infection by dual rabeprazole/amoxicillin therapy depended on the CYP2C19 genotype status. This dual therapy appears to be effective for hetEM and PM patients. However, high dose dual rabeprazole/amoxicillin therapy was effective even for homEM patients. Therefore, the genotyping test of CYP2C19 appears to be a clinically useful tool for the optimal dual treatment with rabeprazole plus amoxicillin. | ||||||||
| 56 | 50.08 | 11443522 | 2001.09.06 | + | + | Mutation analysis of SYNJ1: a possible candidate gene for chromosome 21q22-linked bipolar disorder. | Mol Psychiatry | |
| T Saito, F Guan, DF Papolos, S Lau, M Klein, CS Fann, HM Lachman, | ||||||||
| Genes involved in the regulation of synaptic vesicle function are potential candidates for the development of psychiatric disorders. In addition to experimental and theoretical considerations, a number of genes involved in synaptic vesicle function map to regions of the genome that have been linked to bipolar disorder (BPD) and schizophrenia (SZ). One is synaptojanin 1 (SYNJ1) which maps to 21q22.2, a chromosomal region that has been linked to BPD in a subset of families in several studies. Synaptojanin 1 is an inositol 5-phosphatase that has an important role in synaptic vesicle endocytosis. Mutation screening of 32 exons, intron--exon junctions, and 839 bases of 5'-flanking DNA resulted in the identification of 11 mutations of which four were very common and seven were very rare. Of the 11 mutations identified, several may have functional significance including two coding variants, two that may affect the binding of a transcription factor, and two that involve known splicing regulatory domains. Five bipolar patients out of 149 analyzed were found who have one of the four rare variants that were most likely to have functional significance compared with 0/148 controls. The allele frequencies for three of the four common variants were very similar in bipolar patients and controls. A slight difference in allele frequency was found for an interesting mutation we detected in intron 12 in which two non-adjacent thymidine residues are deleted in a poly-AT tract located near the exon 12 splice donor site (chi(2) = 2.45, P = 0.12, 2-tailed). Although we failed to unequivocally identify a specific SYNJ1 allele that could be responsible for putative chromosome 21q22-linked BPD, several interesting variants were found to be increased in bipolar subjects and should be further investigated. | ||||||||
| 57 | 50.03 | 8946471 | 1997.03.14 | + | + | A new CYP2D6 allele with a nine base insertion in exon 9 in a Japanese population associated with poor metabolizer phenotype. | Pharmacogenetics | |
| T Yokoi, Y Kosaka, M Chida, K Chiba, H Nakamura, T Ishizaki, M Kinoshita, K Sato, FJ Gonzalez, T Kamataki, | ||||||||
| The CYP2D6 gene of a Japanese sparteine poor metabolizer (PM, proband) showing a urinary sparteine metabolic ratio of 31.6 was analysed, and a heterozygous CYP2D6(D), a deletional type, was found by restriction fragment length polymorphism analysis with Xba I enzyme. The PM did not have any other previously described mutations in the CYP2D6 gene causing the loss of catalytic activity of the CYP2D6 enzyme. Thus, a possible new allele(s) responsible for the PM phenotype was analysed. The results indicated that the PM possessed a new 9-base insertion in exon 9, designated CYP2D6(J9). The CYP2D6(J9) and CYP2D6(D) alleles were clarified to be inherited from the mother [2D6(W)/2D6(J9)] and the father [2D6(W)/2D6(D)], respectively. The 9-base insertion caused a large increase in the apparent K(m) value for bufuralol 1'-hydroxylation as examined by expression of the enzyme protein in yeast. Four of 300 Japanese carried a heterozygous CYP2D6(J9) allele (0.7%, 4/600 chromosomes) as determined by a polymerase chain reaction analysis. | ||||||||
| 58 | 50.02 | 16041239 | 2005.10.18 | + | + | Influence of ABCB1, ABCC1, ABCC2, and ABCG2 haplotypes on the cellular exposure of nelfinavir in vivo. | Pharmacogenet Genomics | |
| S Colombo, N Soranzo, M Rotger, R Sprenger, G Bleiber, H Furrer, T Buclin, D Goldstein, L Décosterd, A Telenti, | ||||||||
| OBJECTIVES: The human immunodeficiency virus protease inhibitor nelfinavir is substrate of polyspecific drug transporters encoded by ABCB1 (P-glycoprotein), ABCC1 (MRP1) and ABCC2 (MRP2), and an inhibitor of BCRP, encoded by ABCG2. Genetic polymorphism in these genes may be associated with changes in transport function. METHODS: A comprehensive evaluation of single nucleotide polymorphisms (39 SNPs in ABCB1, 7 in ABCC1, 27 in ABCC2, and 16 in ABCG2), and inferred haplotypes was done to assess possible associations of genetic variants with cellular exposure of nelfinavir in vivo. Analysis used peripheral mononuclear cells from individuals receiving nelfinavir (n=28). Key results were re-examined in a larger sample size (n=129) contributing data on plasma drug levels. RESULTS AND CONCLUSIONS: There was no significant association between cellular nelfinavir area under the curve (AUC) and SNPs or haplotypes at ABCC1, ABCC2, ABCG2. There was an association with cellular exposure for two loci in strong linkage disequilibrium: ABCB1 3435C>T; AUCTT>AUCCT>AUCCC (ratio 2.1, 1.4, 1, Ptrend=0.01), and intron 26 +80T>C; AUCCC> AUCCT > AUCTT (ratio 2.4, 1.3, 1, Ptrend=0.006). Haplotypic analysis using tagging SNPs did not improve the single SNP association values. | ||||||||
| 59 | 50.01 | 15719397 | 2005.05.09 | + | + | The serotonin transporter gene as a QTL for ADHD. | Am J Med Genet B Neuropsychiatr Genet | |
| S Curran, S Purcell, I Craig, P Asherson, P Sham, | ||||||||
| Molecular studies of attention deficit hyperactivity disorder (ADHD) have identified susceptibility genes for the categorically diagnosed disorder using operational diagnostic criteria. Here, we take a QTL approach to mapping genes for ADHD using a composite continuous index of ADHD behavior in a large epidemiological sample. Previous studies of clinical ADHD suggest that two functional polymorphisms in the serotonin transporter gene (SLC6A4), one in the 5'-regulatory region of the gene (5-HTTLPR) and the other a VNTR (5-HTTVNTR) in the second intron, as well as a single nucleotide polymorphism in the 3'-untranslated region (3'-UTR SNP), may be associated with the disorder. Here, we investigate these polymorphisms as well as an additional ten SNPs spread across the gene. We found significant association with the long (L) allele of the 5-HTTLPR; P = 0.019, but neither the 5-HTTVNTR nor the 3'-UTR SNP were significantly associated. Significant associations (P < 0.05) were found for a further 5 the 10 other markers tested. We found evidence for two haplotype blocks spanning the region. We found strong evidence for association with the first haplotype block (comprised of four markers), with the significance of a combined primary and secondary test of association reaching an empirical P value = 0.0054 for the global test and an empirical P value = 0.00081 for the largest local test. Thus, we show here that SLC6A4, which has a major influence on brain serotonin availability, may be a QTL for ADHD. | ||||||||
| 60 | 49.91 | 15052272 | 2004.12.08 | + | + | Investigation of serotonin-related genes in antidepressant response. | Mol Psychiatry | |
| EJ Peters, SL Slager, PJ McGrath, JA Knowles, SP Hamilton, | ||||||||
| In this study, we sought out to test the hypothesis that genetic factors may influence antidepressant response to fluoxetine. The investigation focused on seven candidate genes in the serotonergic pathway involved in the synthesis, transport, recognition, and degradation of serotonin. Our clinical sample consisted of 96 subjects with unipolar major depression treated with fluoxetine with response variables assessed after a 12-week trial. Patient data were also collected to investigate the pattern of drug response. Using a high-throughput single-nucleotide polymorphism (SNP) genotyping platform and capillary electrophoresis, we genotyped patients at 110 SNPs and four repeat polymorphisms located in seven candidate genes (HTR1A, HTR2A, HTR2C, MAOA, SLC6A4, TPH1, and TPH2). Statistical tests performed included single-locus and haplotype association tests, and linkage disequilibrium (LD) estimation. Little evidence of population stratification was observed in the sample with 20 random SNPs using a genomic control procedure. Our most intriguing result involved three SNPs in the TPH1 gene and one SNP in the SLC6A4 gene, which show significant single-locus association when response to fluoxetine is compared to nonresponse (P=0.02-0.04). All odds ratios indicated an increased risk of not responding to fluoxetine. In the specific response vs nonspecific and nonresponse comparison, three SNPs in the TPH2 gene (P=0.02-0.04) were positively associated and one SNP in the HTR2A gene (P=0.02) was negatively associated. When comparing specific response to nonspecific response, we found significant negative associations in three SNPs in the HTR2A gene (P=0.001-0.03) and two SNPs in the MAOA gene (P=0.03-0.05). We observed variable, although strong LD, in each gene and unexpectedly low numbers of estimated haplotypes, formed from tagged SNPs. Significant haplotype associations were found in all but the HTR1A and HTR2C genes. Although these data should be interpreted cautiously due to the small sample size, these results implicate TPH1 and SLC6A4 in general response, and HTR2A, TPH2, and MAOA in the specificity of response to fluoxetine. Intriguingly, we observe that a number of the less frequent alleles of many of the SNP markers were associated with the nonresponse and nonspecific phenotypes. | ||||||||
| 61 | 49.89 | 8845855 | 1996.10.24 | + | + | The pharmacogenetics of codeine hypoalgesia. | Pharmacogenetics | |
| SH Sindrup, K Brøsen, | ||||||||
| Codeine is an old drug that is still widely used to treat mild and moderate pain. It is mainly metabolised by glucuronidation, but minor pathways are N-demethylation to norcodeine and O-demethylation to morphine. The latter pathway depends on the genetically polymorphic CYP2D6 which is absent in 7% of the white population (PM) and present in the remainder (EM). Lack of influence of codeine on experimental pain in PM as well as in EM treated with the CYP2D6 blocker quinidine, who are both practically unable to convert codeine to morphine, has supported an old hypothesis that codeine acts through metabolically formed morphine. Possibly, local codeine O-demethylation in the CNS is of major importance for its hypoalgesic effect. Such a local morphine formation from codeine, which supposedly is also catalysed by CYP2D6, could explain why the hypoalgesic effect of codeine stems from morphine despite relatively low plasma levels of morphine after standard hypoalgesic doses of codeine. Dependence of codeine hypoalgesia on morphine formation via CYP2D6 makes this effect liable to interaction with drugs that are inhibitors of CYP2D6. Examples of potent inhibitors of CYP2D6 are quinidine, some selective serotonin reuptake inhibitors and some neuroleptics. Less potent inhibitors, such as tricyclic antidepressants, will probably also reduce the pain relieving effect of codeine, since codeine has a low affinity for CYP2D6. Biosynthesis of morphine in humans may also include steps catalyse by CYP2D6. Experimental studies in large groups of EM and PM indicate that this may lead to interphenotype differences in pain tolerance. | ||||||||
| 62 | 49.84 | 15864124 | 2005.07.18 | + | + | Genetic polymorphism in the phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity. | Pharmacogenet Genomics | |
| C Kitagawa, M Ando, Y Ando, Y Sekido, K Wakai, K Imaizumi, K Shimokata, Y Hasegawa, | ||||||||
| Genetic polymorphism of the UDP-glucuronosyltransferase (UGT) 1A1 gene is associated with the decreased glucuronidation activity of an active metabolite of irinotecan, SN-38, and UGT1A1*28 has been shown as a predictive factor for irinotecan toxicity. The phenobarbital-responsive enhancer module (PBREM) of the UGT1A1 promoter region has been reportedly associated with the transcriptional activity of the gene. We investigated whether the polymorphism of PBREM (T-3279G) would affect inter-patient variations in sensitivity to irinotecan toxicity. The study population comprised 119 cancer patients who had received irinotecan. We reviewed their clinical records, including patient characteristics, and observed their toxicity levels following irinotecan infusion. Genotyping was performed by sequencing analyses. Logistic regression analyses were performed to assess the relationship between genotypes and irinotecan toxicity. We identified the homozygotes of the reference allele for T-3279G in 68 patients, the heterozygotes in 37, and the homozygotes for the variant in 14. Logistic regression analysis indicated a significant association between the homozygotes for T-3279G and the severe toxicity (odds ratio 5.80; 95% confidence interval 1.67-20.1). However, multivariate analysis, including the data of UGT1A1*28 polymorphism, revealed a diminution of the association due to a highly significant linkage disequilibrium between these polymorphisms. Our results suggest that a highly significant linkage disequilibrium exists between T-3279G and UGT1A1*28 polymorphisms, and that the variants of T-3279G and UGT1A1*28 cooperatively decrease transcriptional activity of the UGT1A1 promoter. The determination of T-3279G and UGT1A1*28 genotypes might be clinically useful in predicting severe irinotecan toxicity in cancer patients. | ||||||||
| 63 | 49.78 | 8807668 | 1996.11.20 | + | + | Evidence that poor metabolizers of (S)-mephenytoin could be identified by haplotypes of CYP2C19 in Japanese. | Pharmacogenetics | |
| F Takakubo, A Kuwano, I Kondo, | ||||||||
| (S)-Mephenytoin is metabolized by CYP2C19. The purpose of this study was to examine availability of phenotyping of poor metabolizers (PMs) of (S)-mephenytoin by polymerase chain reaction (PCR)/restriction enzyme genotyping of CYP2C19 in a Japanese population. We genotyped 217 unrelated healthy Japanese for functionally defective alleles, CYP2C19m1 and CYP2C19m2. The frequencies of the wild type(wm1) and CYP2C19m1 were 0.726 and 0.274, and the wild type(wm2) and CYP2C19m2 were 0.892 and 0.108 respectively. Although the observed numbers of three genotypes were very similar to those estimated according to the Hardy-Weinberg equilibrium for each defect, CYP2C19m2 was not detected in m1 homozygotes, and CYP2C19m1 was not detected in m2 homozygotes. Two defects were inherited separately in four families indicating CYP2C19m1 and m2 segregate independently at the same gene locus. Based on these data, we calculated the haplotype frequencies of wm1-wm2, CYP2C19m1-wm2 and wm1-CYP2C19m2 to be 0.618, 0.274 and 0.108 respectively. Frequencies of homozygotes for CYP2C19m1 and CYP2C19m2 and compound heterozygotes associated with the PM phenotype, were calculated to be 7.5, 1.2 and 5.9% respectively. In total, 14.6% of Japanese are estimated to be PMs. No significant difference was observed between the frequencies of PMs calculated from our results and that identified by urinary S/R ratio (18%) (p > 0.05, chi 2 = 0.545, fd = 1). Our data indicate that Japanese PMs of (S)-mephenytoin could be identified by PCR-based genotyping of CYP2C19. | ||||||||
| 64 | 49.75 | 9693036 | 1998.09.14 | + | + | Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1. | Genomics | |
| I Splawski, J Shen, KW Timothy, GM Vincent, MH Lehmann, MT Keating, | ||||||||
| Long QT syndrome (LQT) is a cardiac disorder causing syncope and sudden death from arrhythmias. LQT is characterized by prolongation of the QT interval on electrocardiogram, an indicationof abnormal cardiac repolarization. Mutations in KVLQT1, HERG, SCN5A, and KCNE1, genes encoding cardiac ion channels, cause LQT. Here, we define thecomplete genomic structure of three LQT genesand use this information to identify disease-associated mutations. KVLQT1 is composed of 16 exonsand encompasses approximately 400 kb. HERG consists of 16 exons and spans 55 kb. Three exons make up KCNE1. Each intron of these genes contains the invariant GT and AG at the donor and acceptor splice sites, respectively. Intron sequences were used to design primer pairs for the amplification of all exons. Familial and sporadic cases affected bymutations in KVLQT1, HERG, and KCNE1 can nowbe genetically screened to identify individuals at risk of developing this disorder. This work has clinical implications for presymptomatic diagnosis and therapy. | ||||||||
| 65 | 49.65 | 7485241 | 1995.12.15 | + | + | No association between schizophrenia and polymorphisms within the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT). | Am J Med Genet | |
| J Daniels, J Williams, P Asherson, P McGuffin, M Owen, | ||||||||
| It has been suggested that the cytochrome P450 mono-oxygenase, debrisoquine 4-hydroxylase, is involved in the catabolism and processing of neurotransmitters subsequent to their reuptake into target cells. It is also thought to be related to the dopamine transporter that acts to take released dopamine back up into presynaptic terminals. The present study used the association approach to test the hypothesis that mutations in the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT) confer susceptibility to schizophrenia. There were no differences in allele or genotype frequencies between patients and controls in the mutations causing the poor metaboliser phenotype in CYP2D6. In addition there was no association found between schizophrenia and a 48bp repeat within the 3' untranslated region of DAT. | ||||||||
| 66 | 49.60 | 10722792 | 2000.05.05 | + | + | Mutation screening of human 5-HT(2B)receptor gene in early-onset obsessive-compulsive disorder. | Mol Cell Probes | |
| SJ Kim, J Veenstra-VanderWeele, GL Hanna, D Gonen, BL Leventhal, EH Cook, | ||||||||
| The serotonin receptor 2B gene (HTR2B; MIM 601122) is a pharmacological and positional candidate gene in early-onset obsessive-compulsive disorder. Sequences of a putative promoter region and splice regions were first elucidated, then sequenced along with HTR2B coding regions. Probands from seven families included in a previous genome scan in which one of the strongest linkage findings was to a region including HTR2B, along with two genomic DNA pools of 10 unrelated control subjects and 10 unrelated autism probands were screened. One single nucleotide polymorphism was found in intron 1, that may be useful as a marker in genetic linkage and association studies. It does not appear likely to affect splicing. No evidence for functional mutation was found in the sequenced regions of HTR2B. | ||||||||
| 67 | 49.57 | 14608356 | 2004.01.05 | + | + | An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. | Nat Genet | |
| S Tokuhiro, R Yamada, X Chang, A Suzuki, Y Kochi, T Sawada, M Suzuki, M Nagasaki, M Ohtsuki, M Ono, H Furukawa, M Nagashima, S Yoshino, A Mabuchi, A Sekine, S Saito, A Takahashi, T Tsunoda, Y Nakamura, K Yamamoto, | ||||||||
| Rheumatoid arthritis is a common inflammatory disease with complex genetic components. We investigated the genetic contribution of the cytokine gene cluster in chromosome 5q31 to susceptibility to rheumatoid arthritis in the Japanese population by case-control linkage disequilibrium (LD) mapping using single nucleotide polymorphisms (SNPs). Here we report that there is significant association between rheumatoid arthritis and the organic cation transporter gene SLC22A4 (P = 0.000034). We show that expression of SLC22A4 is specific to hematological and immunological tissues and that SLC22A4 is also highly expressed in the inflammatory joints of mice with collagen-induced arthritis. A SNP affects the transcriptional efficiency of SLC22A4 in vitro, owing to an allelic difference in affinity to Runt-related transcription factor 1 (RUNX1), a transcriptional regulator in the hematopoietic system. A SNP in RUNX1 is also strongly associated with rheumatoid arthritis (P = 0.00035). Our data indicate that the regulation of SLC22A4 expression by RUNX1 is associated with susceptibility to rheumatoid arthritis, which may represent an example of an epistatic effect of two genes on this disorder. | ||||||||
| 68 | 49.49 | 10483058 | 1999.10.18 | + | + | Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways. | Mol Psychiatry | |
| A Frisch, D Postilnick, R Rockah, E Michaelovsky, S Postilnick, E Birman, N Laor, B Rauchverger, A Kreinin, M Poyurovsky, M Schneidman, I Modai, R Weizman, | ||||||||
| Major depressive disorder (MDD) is a severe psychiatric disorder with a lifetime prevalence of about 15%.1 The importance of the genetic component is well accepted,2 but the mode of inheritance is complex and non-Mendelian. A line of evidence suggests the involvement of serotonin and dopamine neurotransmitters in the pathophysiology of depression. In the present study, 102 unipolar MDD patients and 172 healthy controls were genotyped for polymorphisms in four serotonergic and three dopaminergic candidate genes [tryptophan hydroxylase (TPH), serotonin receptor 2A (HTR2A), serotonin receptor 2C (HTR2C), serotonin transporter promoter region (5-HTTLPR), dopamine receptor D4 (DRD4), dopamine transporter (DAT1) and catechol-O-methyl transferase (COMT)]. There were no statistical differences between MDD patients and healthy controls in the genotypic and allelic distribution of all polymorphisms investigated. Thus, our study does not support a major role for these polymorphisms in contributing to susceptibility to MDD, although it does not preclude minor effects. | ||||||||
| 69 | 49.48 | 16299241 | 2006.02.13 | + | + | Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel. | Clin Cancer Res | |
| A Henningsson, S Marsh, WJ Loos, MO Karlsson, A Garsa, K Mross, S Mielke, L Viganò, A Locatelli, J Verweij, A Sparreboom, HL McLeod, | ||||||||
| PURPOSE: To retrospectively evaluate the effects of six known allelic variants in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes on the pharmacokinetics of the anticancer agent paclitaxel (Taxol). EXPERIMENTAL DESIGN: A cohort of 97 Caucasian patients with cancer (median age, 57 years) received paclitaxel as an i.v. infusion (dose range, 80-225 mg/m(2)). Genomic DNA was analyzed using PCR RFLP or using Pyrosequencing. Pharmacokinetic variables for unbound paclitaxel were estimated using nonlinear mixed effect modeling. The effects of genotypes on typical value of clearance were evaluated with the likelihood ratio test within NONMEM. In addition, relations between genotype and individual pharmacokinetic variable estimates were evaluated with one-way ANOVA. RESULTS: The allele frequencies for the CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP3A4*3, CYP3A5*3C, and ABCB1 3435C>T variants were 0.7%, 9.2%, 2.1%, 0.5%, 93.2%, and 47.1%, respectively, and all were in Hardy-Weinberg equilibrium. The population typical value of clearance of unbound paclitaxel was 301 L/h (individual clearance range, 83.7-1055 L/h). The CYP2C8 or CYP3A4/5 genotypes were not statistically significantly associated with unbound clearance of paclitaxel. Likewise, no statistically significant association was observed between the ABCB1 3435C>T variant and any of the studied pharmacokinetic variables. CONCLUSIONS: This study indicates that the presently evaluated variant alleles in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes do not explain the substantial interindividual variability in paclitaxel pharmacokinetics. | ||||||||
| 70 | 49.42 | 9511178 | 1998.04.21 | + | + | Polymorphism of the Pi class glutathione S-transferase in normal populations and cancer patients. | Pharmacogenetics | |
| MJ Harris, M Coggan, L Langton, SR Wilson, PG Board, | ||||||||
| Deficiencies of the glutathione transferase isoenzymes GSTM1-1 and GSTT1-1 have been shown to be risk modifiers in a number of different cancers but there have been no similar studies with GSTP1-1, the only member of the Pi class of glutathione S-transferases expressed in humans. Over-expression of GSTP1-1 in tumours suggests that it may be a significant factor in acquired resistance to certain anticancer drugs. We previously identified a cDNA clone with two amino acid substitutions (I105V, A114V). This clone suggests that the GSTP1 gene is polymorphic and it is possible that the different genotypes may be associated with altered cancer risk or drug resistance. In the present study, we report methods for genotyping individuals at codons 105 and 114 of GSTP1 and demonstrate that these two loci are polymorphic in several different racial groups. We also detected significant linkage disequilibrium between these two loci. To determine if either of the alleles at these two loci were associated with altered cancer susceptibility, we genotyped individuals with colorectal cancer or lung cancer. A total of 131 colorectal and 184 lung cancer patients were compared with 199 control individuals. Overall, there were no significant associations between the GSTP1 polymorphisms and either form of cancer. | ||||||||
| 71 | 49.40 | 12479221 | 2003.01.08 | + | + | C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance. | Mol Cancer Ther | |
| Y Imai, M Nakane, K Kage, S Tsukahara, E Ishikawa, T Tsuruo, Y Miki, Y Sugimoto, | ||||||||
| Breast cancer resistance protein (BCRP) confers multidrug resistance to cancer cells against agents such as SN-38 (an active metabolite of irinotecan), mitoxantrone, and topotecan. Among 59 human tumor cell lines tested, 6 cell lines, A549, NCI-H460, KM-12, HT-29, OVCAR-5, and RPMI8226, showed high BCRP expression. BCRP cDNA was isolated from 11 cancer cell lines and three variant cDNAs [G34A substituting Met for Val-12 (V12M), C421A substituting Lys for Gln-141 (Q141K), and 944-949 deletion lacking Ala-315 and Thr-316 (delta315-6)] were identified. G34A and C421A variants were polymorphisms, and 944-949 deletion was a splicing variant. C421A BCRP-transfected PA317 cells showed markedly decreased protein expression and low-level drug resistance compared with wild-type BCRP-transfected cells when transfectants expressed similar levels of BCRP mRNA. G34A or 944-949-deleted BCRP-transfected PA317 cells showed similar or somewhat lower protein expression and drug resistance compared with wild-type BCRP-transfected cells. Of 124 healthy Japanese volunteers, 67 were wild-type, 48 were heterozygous, and 9 were homozygous for the C421A allele. These results suggest that some people possess the C421A polymorphic BCRP gene and express low amounts of Q141K BCRP. In addition to that, C376T polymorphism in exon 4 substituting stop codon for Gln-126 was found in 3 of the 124 general Japanese population. This C376T polymorphism may also have high impact because active BCRP protein will not be expressed from the C376T allele. Therefore, people with C376T and/or C421A polymorphisms may express low amounts of BCRP, and this low BCRP expression might result in hypersensitivity of normal cells to such anticancer drugs as irinotecan and mitoxantrone. | ||||||||
| 72 | 49.23 | 10391666 | 1999.07.09 | + | + | Theophylline pharmacokinetics are not altered by lansoprazole in CYP2C19 poor metabolizers. | Clin Pharmacol Ther | |
| JW Ko, IJ Jang, JG Shin, SK Nam, SG Shin, DA Flockhart, | ||||||||
| Lansoprazole is a potent gastric proton pump inhibitor that is metabolized by CYP2C19 but appears to induce the activity of hepatic microsomal CYP1A2 in a concentration-dependent manner. Because the inducing effect appears to be a dose-dependent phenomenon, it may be more important in poor metabolizers of CYP2C19 who have more than four times the area under the lansoprazole plasma concentration-time curve (AUC) and constitute 12% to 23% of Asian populations. Theophylline owes a significant portion of its metabolism to CYP1A2 and can cause gastric acid reflux that calls for concurrent use of proton pump inhibitors. We conducted a prospective, randomized, subject-blind, multicenter crossover study of the effect of multiple high-dose oral lansoprazole (30 mg twice a day for 7 days) on the pharmacokinetics of a single intravenous dose of theophylline (4.73 mg/kg) in healthy volunteers characterized for CYP2C19 genotype. The study compared the pharmacokinetics of lansoprazole and theophylline in five white extensive metabolizers, six Korean extensive metabolizers, and seven poor metabolizers of CYP2C19. The pharmacokinetics of lansoprazole were significantly different among groups; AUC values were 1.55+/-0.20 microg x h/mL in white extensive metabolizers, 7.01+/-0.72 microg x hr/mL in Korean extensive metabolizers, and 14.34+/-2.60 microg x h/mL in poor metabolizers (P < .001). The administration of lansoprazole did not change intravenous theophylline clearance compared with placebo in any group, and theophylline clearance exhibited no correlation with AUC of lansoprazole (rs = 0.12; P > .1). These data suggest that usual therapeutic doses of lansoprazole have no clinically significant influence on the clearance of theophylline, even in poor metabolizers of CYP2C19. | ||||||||
| 73 | 49.20 | 12068375 | 2002.07.26 | + | + | Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L. | Am J Hum Genet | |
| D Watkins, M Ru, HY Hwang, CD Kim, A Murray, NS Philip, W Kim, H Legakis, T Wai, JF Hilton, B Ge, C Doré, A Hosack, A Wilson, RA Gravel, B Shane, TJ Hudson, DS Rosenblatt, | ||||||||
| Mutations in the MTR gene, which encodes methionine synthase on human chromosome 1p43, result in the methylcobalamin deficiency G (cblG) disorder, which is characterized by homocystinuria, hyperhomocysteinemia, and hypomethioninemia. To investigate the molecular basis of the disorder, we have characterized the structure of the MTR gene, thereby identifying exon-intron boundaries. This enabled amplification of each of the 33 exons of the gene, from genomic DNA from a panel of 21 patients with cblG. Thirteen novel mutations were identified. These included five deletions (c.12-13delGC, c.381delA, c.2101delT, c.2669-2670delTG, and c.2796-2800delAAGTC) and two nonsense mutations (R585X and E1204X) that would result in synthesis of truncated proteins that lack portions critical for enzyme function. One mutation was identified that resulted in conversion of A to C of the invariant A of the 3' splice site of intron 9. Five missense mutations (A410P, S437Y, S450H, H595P, and I804T) were identified. The latter mutations, as well as the splice-site mutation, were not detected in a panel of 50 anonymous DNA samples, suggesting that these sequence changes are not polymorphisms present in the general population. In addition, a previously described missense mutation, P1173L, was detected in 16 patients in an expanded panel of 24 patients with cblG. Analysis of haplotypes constructed using sequence polymorphisms identified within the MTR gene demonstrated that this mutation, a C-->T transition in a CpG island, has occurred on at least two separate genetic backgrounds. | ||||||||
| 74 | 49.09 | 9492390 | 1998.04.02 | + | + | Cytochrome P450 2C9 catalyzes indomethacin O-demethylation in human liver microsomes. | Drug Metab Dispos | |
| M Nakajima, T Inoue, N Shimada, S Tokudome, T Yamamoto, Y Kuroiwa, | ||||||||
| Indomethacin is a widely used nonsteroidal anti-inflammatory drug. We studied the human cytochrome P450 (CYP) isoform responsible for indomethacin O-demethylation, the major metabolic pathway for indomethacin. For indomethacin O-demethylase activities, the KM value was 34.6 +/- 5.4 muM and the Vmax value was 14.1 +/- 3.9 pmol/mg/min in human liver microsomes (N = 4). Indomethacin O-demethylase activity in human liver microsomes was competitively inhibited by sulfaphenazole, (S)-warfarin, and tolbutamide and was not affected by alpha-naphthoflavone, (S)-mephenytoin, or erythromycin. Indomethacin O-demethylase activities in microsomes from nine human livers were significantly correlated with tolbutamide hydroxylase activities (r = 0.750, p < 0.05) and not with (S)-mephenytoin 4'-hydroxylase activities. When the capacity for indomethacin O-demethylation in microsomes of B lymphoblastoid cells expressing human CYPs was investigated at an indomethacin concentration of 5 microM, cDNA-expressed CYP2C9 exhibited 6-fold greater activity than did CYP2C19. At an indomethacin concentration of 50 microM, cDNA-expressed CYP1A2 and CYP2D6 also exhibited slight activities. The KM values were 9.9 +/- 1.2 and 117.1 +/- 13.8 microM and the Vmax values were 0.33 +/- 0.05 and 0.24 +/- 0.04 pmol/min/pmol CYP in microsomes with cDNA-expressed CYP2C9 and CYP2C19, respectively (N = 4). Considering the 16-fold higher intrinsic clearance of CYP2C9, compared with that of CYP2C19, and these expression levels in human livers, the contribution of CYP2C19 to indomethacin O-demethylation was considered to be negligible. Indomethacin appears to be O-demethylated exclusively by CYP2C9 in humans. | ||||||||
| 75 | 49.05 | 16100021 | 2006.01.12 | + | + | Association of apolipoprotein E4 and haplotypes of the apolipoprotein E gene with lobar intracerebral hemorrhage. | Stroke | |
| D Woo, R Kaushal, R Chakraborty, J Woo, M Haverbusch, P Sekar, B Kissela, A Pancioli, E Jauch, D Kleindorfer, M Flaherty, A Schneider, P Khatri, L Sauerbeck, J Khoury, R Deka, J Broderick, | ||||||||
| BACKGROUND AND PURPOSE: Conflicting reports in the literature exist with regard to the association of apolipoprotein E (apo E) alleles and lobar intracerebral hemorrhage (ICH). We genotyped 12 single-nucleotide polymorphisms in the 5' upstream regulatory, exonic, and intronic regions of the apo E gene and performed genotype and haplotype association analyses. METHODS: We prospectively enrolled subjects with hemorrhagic stroke and matched them with 2 controls based on age, race, and sex. Each case was reviewed by a physician to determine case status and location of the ICH. Multivariate logistic-regression modeling with backward elimination was used to determine significant risk factors for lobar ICH. Associations at the genotype and haplotype levels and linkage disequilibrium were conducted according to standard statistical methods. RESULTS: Between May 1997 and December 2002, 315 cases of ICH were recruited, of whom 107 were lobar ICH cases matched to 205 controls. No association was found for apo E2, E3, or E4 with nonlobar ICH. Independent, significant risk factors for lobar ICH included apo E4, untreated hypertension, anticoagulant use, a first-degree relative with ICH, and < or =high school education (compared with >high school education). Treated hypercholesterolemia compared with "no history of hypercholesterolemia" was associated with a decreased risk of lobar ICH. Haplotype association analysis demonstrated a significant association of the apo E gene with lobar ICH among whites (P<0.0001) and blacks (P=0.0024). CONCLUSIONS: Apo E4 is independently associated with lobar ICH but not nonlobar ICH. Haplotypes of the apo E gene are associated with lobar ICH. Untreated hypertension is a risk factor for lobar ICH. | ||||||||
| 76 | 48.99 | 10850388 | 2000.09.22 | + | + | Catalytic activity of three variants (Ile, Leu, and Thr) at amino acid residue 359 in human CYP2C9 gene and simultaneous detection using single-strand conformation polymorphism analysis. | Ther Drug Monit | |
| I Ieiri, H Tainaka, T Morita, A Hadama, K Mamiya, M Hayashibara, H Ninomiya, S Ohmori, M Kitada, N Tashiro, S Higuchi, K Otsubo, | ||||||||
| This study evaluated the catalytic activity of three variants (Ile, Leu, and Thr) at codon 359 of CYP2C9 enzymes expressed in a yeast cDNA expression system, and then established single-strand conformation polymorphism (PCR-SSCP) analysis for simultaneous detection as a screening method. Diclofenac was used for the in vitro experiment, and its hydroxy metabolite (4'-hydroxydiclofenac) was measured by HPLC. To discuss the in vivo effect of the Thr359 variant on the pharmacokinetics of phenytoin, a case report is presented. The efficiency of the SSCP method was evaluated by analyzing DNA samples from a homozygote for Ile359 and a heterozygote for Leu359 or Thr359. To evaluate the interaction between the P450 level and reductase activity, two batches of the Thr359 variant with a different P450:reductase activity ratio (1:4.0 and 1:1.4) were used. The in vitro study revealed that recombinant Ile359, Leu359, and Thr359 (2 batches) possessed a mean Km of 2.0, 16.5 and (3.8 and 2.9) micromol and Vmax of 12.4, 17.9 and (4.4 and 5.1) nmol/min/nmol P450, respectively. Although the magnitude of the change in catalytic efficiency for the Thr359 variant was close to that of the Leu359 variant, the effect of the two variants on diclofenac 4'-hydroxylation appears to be different because Leu359 variant was associated with a high Km, and Thr359 with a low Vmax. No significant differences in the kinetic data were observed between the two Thr359 enzymes, suggesting that low reductase activity in the Thr359 enzyme was not a major determinant in the present in vitro experiment. Estimated pharmacokinetic parameters of phenytoin obtained by the Bayesian method in an epileptic patient who was a heterozygote carrier for Thr359 variant were: Km = 6.45 microg/mL, Vmax = 5.77 mg/kg/d, and Vmax/Km = 0.89 L/kg/day. The Vmax/Km value in this patient was similar to the population mean value (0.90 L/kg/day) in Japanese heterozygotes for the Leu359 variant. Results for PCR-SSCP were in complete agreement with those obtained using established methods. Thus, the PCR-SSCP approach is useful for identifying these three variants of the CYP2C9 gene. | ||||||||
| 77 | 48.95 | 15145965 | 2004.09.20 | + | + | Omeprazole as a CYP2C19 marker in Chinese subjects: assessment of its gene-dose effect and intrasubject variability. | J Clin Pharmacol | |
| OQ Yin, B Tomlinson, AH Chow, MM Waye, MS Chow, | ||||||||
| The objective of this study was to determine the reliability of omeprazole as a marker for CYP2C19 activity in Chinese subjects. In 27 healthy male Chinese subjects, the CYP2C19 phenotype was first determined with the standard mephenytoin hydroxylation index (HI) method. Subsequently, the subjects were randomized in a three-way crossover manner to receive an oral 40-mg dose from each of three omeprazole formulations (as part of a bioequivalence study). Multiple blood samples were obtained over 12 hours, and plasma concentrations of omeprazole, 5-hydroxyomeprazole, and omeprazole sulfone were determined by a high-performance liquid chromatography (HPLC) method. Individual CYP2C19 genotype was determined by the polymerase chain reaction/restriction fragment length polymorphism method. To assess the specificity for CYP2C19 activity, the hydroxylation metabolic ratio (MR) of omeprazole (AUC(omeprazole)/AUC(5-hydroxyomeprazole)) was compared to mephenytoin HI and related to CYP2C19 genotype status. The inter- and intrasubject variabilities of MR were also calculated, and their magnitudes were compared. The intersubject MR varied more than 20 fold. Among the subjects, there was a gene-dose effect, and the mean MR was 1.76, 3.45, and 33.08, respectively, in the homozygous extensive metabolizers (wt/wt, n = 9), heterozygous extensive metabolizers (wt/m1 or wt/m2, n = 10), and poor metabolizers (m1/m1 or m1/m2, n = 7). However, the coefficients of variation for intrasubject MR only ranged from 4.5% to 33.7% over the three periods with the three formulations. The phenotype based on MR was concordant with HI. In view of the clear gene-dose effect, concordance with mephenytoin HI, and low intrasubject variability, omeprazole MR following a 40-mg oral dose can be considered as a specific and sensitive marker for CYP2C19 activity in Chinese subjects. | ||||||||
| 78 | 48.95 | 11851639 | 2002.04.19 | + | + | Effect of chronic disulfiram administration on the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and N-acetyltransferase in healthy human subjects. | Br J Clin Pharmacol | |
| RF Frye, RA Branch, | ||||||||
| AIMS: Short-term disulfiram administration has been shown to selectively inhibit CYP2E1 activity but the effects of chronic disulfiram administration on the activities of drug metabolizing enzymes is unclear. The purpose of this study was to evaluate the effects of disulfiram given for 11 days on selected drug metabolizing enzyme activities. METHODS: Seven healthy volunteers were given disulfiram 250 mg daily for 11 days. Activities of the drug metabolizing enzymes CYP1A2, CYP2C19, CYP2D6, CYP2E1 and N-acetyltransferase were determined using the probe drugs caffeine, mephenytoin, debrisoquine, chlorzoxazone, and dapsone, respectively. Chlorzoxazone was administered before disulfiram administration and after the second and eleventh doses of disulfiram, while the other probe drugs were given before disulfiram administration and after the eleventh disulfiram dose. RESULTS: Disulfiram administration markedly inhibited chlorzoxazone 6-hydroxylation by more than 95%, but did not affect metabolism of debrisoquine or mephenytoin. Caffeine N3-demethylation was decreased by 34% (P < 0.05). Monoacetyldapsone concentrations were markedly elevated by disulfiram administration resulting in a nearly 16-fold increase in the dapsone acetylation index, calculated as the plasma concentration ratio of monoacetyldapsone to dapsone. CYP-mediated dapsone N-hydroxylation was not significantly altered. CONCLUSIONS: These data suggest that disulfiram-mediated inhibition is predominantly selective for CYP2E1. The magnitude of CYP2E1 inhibition was similar after both acute and chronic disulfiram administration. The effects on caffeine N3-demethylation (CYP1A2) and dapsone metabolism suggest that chronic disulfiram administration may affect multiple drug metabolizing enzymes, which could potentially complicate the use of chronically administered disulfiram as a diagnostic inhibitor of CYP2E1. | ||||||||
| 79 | 48.72 | 11803447 | 2002.04.19 | + | + | Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder. | Mol Psychiatry | |
| C Betancur, M Corbex, C Spielewoy, A Philippe, JL Laplanche, JM Launay, C Gillberg, MC Mouren-Siméoni, M Hamon, B Giros, M Nosten-Bertrand, M Leboyer, | ||||||||
| Previous studies have provided conflicting evidence regarding the association of the serotonin transporter (5-HTT) gene with autism. Two polymorphisms have been identified in the human 5-HTT gene, a VNTR in intron 2 and a functional deletion/insertion in the promoter region (5-HTTLPR) with short and long variants. Positive associations of the 5-HTTLPR polymorphism with autism have been reported by two family-based studies, but one found preferential transmission of the short allele and the other of the long allele. Two subsequent studies failed to find evidence of transmission disequilibrium at the 5-HTTLPR locus. These conflicting results could be due to heterogeneity of clinical samples with regard to serotonin (5-HT) blood levels, which have been found to be elevated in some autistic subjects. Thus, we examined the association of the 5-HTTLPR and VNTR polymorphisms of the 5-HTT gene with autism, and we investigated the relationship between 5-HTT variants and whole-blood 5-HT. The transmission/disequilibrium test (TDT) revealed no linkage disequilibrium at either loci in a sample of 96 families comprising 43 trios and 53 sib pairs. Furthermore, no significant relationship between 5-HT blood levels and 5-HTT gene polymorphisms was found. Our results suggest that the 5-HTT gene is unlikely to play a major role as a susceptibility factor in autism. | ||||||||
| 80 | 48.69 | 9110362 | 1997.07.24 | + | + | Allelic and functional variability of cytochrome P4502C9. | Pharmacogenetics | |
| CR Bhasker, JO Miners, S Coulter, DJ Birkett, | ||||||||
| Single nucleotide substitutions are known to result in a different amino acid at one of four sites in cytochrome P4502C9 (CYP2C9) namely: residue 144: Arg/Cys; residue 358: Tyr/Cys; residue 359: Ile/Leu and residue 417: Gly/Asp. Polymerase chain reaction (PCR)-based amplification of the nucleotide fragments encompassing the four residues (144, 358-359 and 417) in 18 samples of human genomic DNA from a liver bank and one sample of DNA extracted from the blood of a known poor metabolizer of tolbutamide has been carried out. The products of PCR amplification were analysed by either allele-specific restriction endonucleases or probed with radioactively labelled allele-specific oligonucleotides in dot blot hybridizations. Fourteen individuals were homozygous for Arg144 and four were heterozygous Arg/Cys144. All individuals analysed were homozygous for Tyr358 (n = 17) and for Gly417 (n = 18). With the exception of one heterozygote the other 17 subjects were homozygous for Ile359. The genotype of the known poor metabolizer of tolbutamide was homozygous for Arg144, Leu359 and Gly417. The relative levels of expression of the Cys and Arg144 alleles was studied in the heterozygotes. A relative 5- to 10-fold greater expression of the Cys- over the Arg144 allele was noted in two heterozygotes. There was no apparent correlation of genotype to the hydroxylation of the known CYP2C9 substrates phenytoin, tolbutamide, torasemide and diclofenac. Apparent K(m) values for the cDNA-expressed Arg144/Ile359, Cys144/ Ile359 and Arg144/Leu359 variants towards tolbutamide were 91 microM, 62 microM and 229 microM, respectively. It is likely that functional changes occurring as a result of the Ile359Leu transition are responsible for the tolbutamide poor metabolizer phenotype. | ||||||||
| 81 | 48.65 | 12154035 | 2002.09.11 | + | + | Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway. | Cancer Res | |
| A Rapisarda, B Uranchimeg, DA Scudiero, M Selby, EA Sausville, RH Shoemaker, G Melillo, | ||||||||
| Hypoxia-inducible factor 1 (HIF-1) is a master regulator of the transcriptional response to oxygen deprivation. HIF-1 has been implicated in the regulation of genes involved in angiogenesis [e.g., vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase] and anaerobic metabolism (e.g., glycolytic enzymes). HIF-1 is essential for angiogenesis and is associated with tumor progression. In addition, overexpression of HIF-1 alpha has been demonstrated in many common human cancers. Therefore, HIF-1 is an attractive molecular target for development of novel cancer therapeutics. We have developed a cell-based high-throughput screen for the identification of small molecule inhibitors of the HIF-1 pathway. We have genetically engineered U251 human glioma cells to stably express a recombinant vector in which the luciferase reporter gene is under control of three copies of a canonical hypoxia-responsive element (U251-HRE). U251-HRE cells consistently expressed luciferase in a hypoxia- and HIF-1-dependent fashion. We now report the results of a pilot screen of the National Cancer Institute "Diversity Set," a collection of approximately 2000 compounds selected to represent the greater chemical diversity of the National Cancer Institute chemical repository. We found four compounds that specifically inhibited HIF-1-dependent induction of luciferase but not luciferase expression driven by a constitutive promoter. In addition, these compounds inhibited hypoxic induction of VEGF mRNA and protein expression in U251 cells. Interestingly, three compounds are closely related camptothecin analogues and topoisomerase (Topo)-I inhibitors. We show that concomitant with HIF-1 and VEGF inhibition, the activity of the Topo-I inhibitors tested is associated with induction of cyclooxygenase 2 mRNA expression. The luciferase-based high-throughput screen is a feasible tool for the identification of small molecule inhibitors of HIF-1 transcriptional activation. In addition, our results suggest that altered Topo-I function may be associated with repression of HIF-1-dependent induction of gene expression. | ||||||||
| 82 | 48.64 | 12709788 | 2003.08.14 | + | + | ABCA1 gene polymorphisms and their associations with coronary artery disease and plasma lipids in males from three ethnic populations in Singapore. | Hum Genet | |
| JH Tan, PS Low, YS Tan, MC Tong, N Saha, H Yang, CK Heng, | ||||||||
| Mutations in the ATP-binding cassette transporter ABCA1 underlie Tangier disease and familial hypoalphaliproteinemia (FHA), disorders that are characterised by reduced high-density lipoprotein-cholesterol (HDL-C) concentration and cholesterol efflux, and increased coronary artery disease (CAD). We explored if polymorphisms in the ABCA1 gene are associated with CAD and variations in plasma lipid levels, especially HDL-C, and whether the associations may depend on ethnicity. Male cases and controls from the Singapore Chinese, Malay and Indian populations were genotyped for five ABCA1 single nucleotide polymorphisms. Various single-locus frequency distribution differences between cases and controls were detected in different ethnic groups: the promoter -14C>T in Indians, exon 18 M883I in Malays, and 3'-untranslated (UTR) region 8994A>G in Chinese. For the Malay population, certain haplotypes carrying the I825- A (exon 17) and M883- G alleles were more frequent among cases than controls, whereas the converse was true for the alternative configuration of V825- G and I883- A, and this association was reinforced in multi-locus disequilibrium analysis that utilized genotypic data. In the healthy controls, associations were found for -14C>T genotypes with HDL-C in Chinese; 237indelG (5'UTR) with apolipoprotein A1 (apoA1) in Malays and total cholesterol (TC) in Indians; M883I with lipoprotein(a) [Lp(a)] in Malays and apolipoprotein B (apoB) in Chinese; and 8994A>G with Lp(a) in Malays, and TC, low-density lipoprotein-cholesterol (LDL-C) as well as apoB in Indians. While genotype-phenotype associations were not reproduced across populations and loci, V825I and M883I were clearly associated with CAD status in Malays with no effects on HDL-C or apoA1. | ||||||||
| 83 | 48.61 | 11717182 | 2002.01.31 | + | + | Population distribution of human flavin-containing monooxygenase form 3: gene polymorphisms. | Drug Metab Dispos | |
| JR Cashman, J Zhang, J Leushner, A Braun, | ||||||||
| The N-oxygenation of amines by the human flavin-containing monooxygenase (form 3) (FMO3) represents an important means for the conversion of lipophilic nucleophilic heteroatom-containing compounds into more polar and readily excreted products. Certain mutations of the human FMO3 gene have been linked to abnormal drug or chemical metabolism. For example, abnormal N-oxygenation of trimethylamine has been shown to segregate with mutations of human FMO3. To date, however, it is not known whether there is a pharmacogenetic basis for abnormal drug metabolism by human FMO3. The objective of this study was to estimate the allele and genotype frequencies at three variable DNA sites in the FMO3 gene in male and female blood bank donors representative of non-Hispanic Caucasians, non-Hispanic African Americans, Hispanics, and Asians sampled from the United States. The common polymorphisms at variable sites 158, 257, and 308 were experimentally determined using a high-throughput chip-based genotype variation detection method combining MassEXTEND and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. We also compared the genetic variation of nonhuman primate FMO3 with the human FMO3 gene. Exon sequence analysis of the monkey FMO3 gene sequence showed that it was similar to the human gene sequence but differed from the human consensus sequence at 31 fixed positions. Compared with that of human, the chimpanzee exon sequence had one polymorphism that induced an amino acid change. The evolutionary history of the FMO3 gene was inferred from the pattern of haplotype relationships across different populations and species. Statistically significant heterogeneity in the relative frequencies of single and multiple site alleles, haplotypes, and genotypes of the human FMO3 among ethnic subdivisions suggests that population differences in the susceptibility of humans to abnormal metabolism or adverse drug reactions for chemicals metabolized by human FMO3 could exist. | ||||||||
| 84 | 48.48 | 8100167 | 1993.07.27 | + | + | Quinidine inhibition of debrisoquine S(+)-4- and 7-hydroxylations in Chinese of different CYP2D6 genotypes. | Pharmacogenetics | |
| L Bertilsson, CO Meese, QY Yue, ML Dahl, M Ingelman-Sundberg, I Johansson, J Säwe, M Eichelbaum, | ||||||||
| Pronounced differences in the CYP2D6 gene between Chinese and Caucasians have previously been described. There was a low frequency of detrimental mutations in the Chinese CYP2D6 gene causing the poor metabolizer (PM) phenotype. In contrast to Caucasians where the Xba I 44 kb allele is almost always associated with the PM phenotype, Chinese with the 44/44 kb RFLP pattern are extensive metabolizers (EM). In order to evaluate whether the debrisoquine hydroxylation seen in subjects with this haplotype is catalysed by a functionally similar enzyme to CYP2D6 or is catalysed by another type of P450 isozyme, product selectivity of the 4-hydroxylation was studied in 27 Chinese. The inhibition of CYP2D6 by quinidine was also investigated. In the 26 Chinese EM the S(+)-4-hydroxy enantiomer was found to be the major urinary metabolite of debrisoquine with an enantiomeric excess of 96.8-100%, which is similar to that in Caucasians. A correlation between the amount of S(+)-4-hydroxy and the minor 7-hydroxy metabolites excreted in urine (r = 0.72; p < 0.001) was seen. The amount of these two metabolites excreted was less in Chinese EM of debrisoquine with the 44/44 kb RFLP pattern, than in those with the wild type 29/29 kb pattern (p < 0.01). The stereoselectivity was very high in both groups. All Chinese homozygous for the 44 kb fragment (n = 5) were transformed to apparent PM after a single 100 mg dose of quinidine similarly to five Caucasian EM. Both the S(+)-4- and 7-hydroxylations of debrisoquine were inhibited by quinidine in both populations. This study shows that the cytochrome P450 catalysing the 4- and 7-hydroxylations of debrisoquine in Chinese EM has the same properties (product stereoselectivity and inhibition by quinidine) as the CYP2D6 in Caucasian EM. | ||||||||
| 85 | 48.36 | 15116053 | 2004.05.27 | + | + | Pharmacogenetics of acenocoumarol pharmacodynamics. | Clin Pharmacol Ther | |
| S Morin, L Bodin, MA Loriot, HH Thijssen, A Robert, S Strabach, C Verstuyft, DA Tregouet, L Dubert, P Laurent-Puig, C Funck-Brentano, P Jaillon, PH Beaune, L Becquemont, | ||||||||
| OBJECTIVE: The aim of this study was to investigate the respective contribution of the different cytochrome P450 (CYP) 2C9 genetic polymorphisms to the interindividual variability of acenocoumarol pharmacodynamic response. METHODS: A total of 263 healthy volunteers were genotyped for CYP2C9*2, CYP2C9*3, CYP2C9*4, and CYP2C9*5 alleles, as well as for the nicotinamide adenine dinucleotide phosphate, reduced, quinone oxidoreductase 1 genetic polymorphism (NQO1*2). Moreover, the 5'-flanking region of the CYP2C9 gene was investigated for new polymorphisms, and haplotype analysis was then performed. Finally, CYP2C9 phenotype was evaluated after a single oral dose of 4 mg of acenocoumarol. Factor VII coagulant activity was measured before and 24 hours after acenocoumarol intake. RESULTS: The CYP2C9*3 allele was the only nonsynonymous single nucleotide polymorphism (SNP) influencing acenocoumarol pharmacodynamics; the percentages of remaining factor VII were 60% +/- 19%, 39% +/- 17%, and 17% for CYP2C9*1/CYP2C9*1, CYP2C9*1/CYP2C9*3, and CYP2C9*3/CYP2C9*3 subjects, respectively (P =.001). Among the white subjects, the CYP2C9 promoter showed the existence of 6 SNPs at positions G-1538A, T-1189C, G-1097A, G-982A, T-640 del, and G-620T with allelic frequencies of 0.085, 0.0398, 0.136, 0.086, 0.005, and 0.0138, respectively. Four major haplotypes could be inferred among white subjects. The haplotype that contains the CYP2C9*3 allele was the only one influencing acenocoumarol pharmacodynamics, explaining 14.3% of its interindividual variability. Body weight explained 5% of acenocoumarol pharmacodynamic variability, whereas the NQO1*2 allele had no significant effect. CONCLUSION: Overall, CYP2C9-related genetic variability accounts for 14% of the interindividual variability in acenocoumarol pharmacodynamic response. The information found by haplotype analysis is mainly related to the CYP2C9*3 SNP. | ||||||||
| 86 | 48.29 | 12891223 | 2003.08.28 | + | + | Celecoxib inhibits metabolism of cytochrome P450 2D6 substrate metoprolol in humans. | Clin Pharmacol Ther | |
| U Werner, D Werner, T Rau, MF Fromm, B Hinz, K Brune, | ||||||||
| OBJECTIVE: In vitro data have shown that celecoxib inhibits the metabolism of cytochrome P450 (CYP) 2D6 substrates. However, very limited data are available on the influence of cyclooxygenase 2 inhibitors on the disposition of CYP2D6 substrates in humans. Therefore the objective of this study was to examine the effect of celecoxib and rofecoxib on the pharmacokinetics of the clinically relevant CYP2D6 substrate metoprolol. METHODS: An open, randomized, 3-period crossover study was performed in 12 healthy male volunteers. Metoprolol (50 mg) was given in all 3 periods without or after 7 days of pretreatment with celecoxib (200 mg twice daily) or rofecoxib (25 mg daily) to achieve steady-state conditions of cyclooxygenase 2 inhibitors in periods 2 and 3. RESULTS: Celecoxib significantly increased the area under the plasma concentration-time curve of metoprolol from 271 to 414 micro g. h/L (64% +/- 57%, P <.001) and by more than 200% in 1 volunteer. The extent of this drug interaction was more pronounced in volunteers with 2 fully functional alleles compared with volunteers with 1 fully functional allele (103% +/- 75% versus 36% +/- 23%, P <.05). After administration of celecoxib, the area under the plasma concentration-time curve from 0 to 24 hours of alpha-hydroxymetoprolol decreased significantly from 474 to 387 micro g. h/L (P <.01). Rofecoxib caused no significant effects on the pharmacokinetics of metoprolol. CONCLUSION: We conclude that celecoxib inhibits the metabolism of the CYP2D6 substrate metoprolol but that rofecoxib does not. Clinically relevant drug interaction may occur between celecoxib and CYP2D6 substrates, particularly those with a narrow therapeutic index. | ||||||||
| 87 | 48.28 | 10323242 | 1999.05.21 | + | + | Molecular characterization of germline mutations in the BRCA1 and BRCA2 genes from breast cancer families in Taiwan. | Hum Genet | |
| SS Li, HM Tseng, TP Yang, CH Liu, SJ Teng, HW Huang, LM Chen, HW Kao, JH Chen, JN Tseng, A Chen, MF Hou, TJ Huang, HT Chang, KT Mok, JH Tsai, | ||||||||
| A total of 18 families with multiple cases of breast cancer were identified from southern Taiwan, and 5 of these families were found to carry cancer-associated germline mutations in the BRCA1 and BRCA2 genes. One novel cryptic splicing mutation of the BRCA1 gene, found in two unrelated families, was shown to be a deletion of 10 bp near the branch site in intron 7. This mutation causes an insertion of 59 nucleotides derived from intron 7 and results in a frameshift, leading to premature translational termination of BRCA1 mRNA in exon 8. Deletions of 2670delC, 3073delT and 6696-7delTC in the BRCA2 gene were found in three other breast cancer families. All three deletions are predicted to generate frameshifts and to result in the premature termination of BRCA2 protein translation. Several genetic polymorphisms in both BRCA1 and BRCA2 genes were also detected in this investigation. | ||||||||
| 88 | 48.27 | 15107849 | 2004.05.25 | + | + | Functional variants of OCTN cation transporter genes are associated with Crohn disease. | Nat Genet | |
| VD Peltekova, RF Wintle, LA Rubin, CI Amos, Q Huang, X Gu, B Newman, M Van Oene, D Cescon, G Greenberg, AM Griffiths, PH St George-Hyslop, KA Siminovitch, | ||||||||
| Crohn disease is a chronic, inflammatory disease of the gastrointestinal tract. A locus of approximately 250 kb at 5q31 (IBD5) was previously associated with susceptibility to Crohn disease, as indicated by increased prevalence of a risk haplotype of 11 single-nucleotide polymorphisms among individuals with Crohn disease, but the pathogenic lesion in the region has not yet been identified. We report here that two variants in the organic cation transporter cluster at 5q31 (a missense substitution in SLC22A4 and a G-->C transversion in the SLC22A5 promoter) form a haplotype associated with susceptibility to Crohn disease. These variants alter transcription and transporter functions of the organic cation transporters and interact with variants in another gene associated with Crohn disease, CARD15, to increase risk of Crohn disease. These results suggest that SLC22A4, SLC22A5 and CARD15 act in a common pathogenic pathway to cause Crohn disease. | ||||||||
| 89 | 48.26 | 9731719 | 1998.11.13 | + | + | Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians. | Pharmacogenetics | |
| K Droll, K Bruce-Mensah, SV Otton, A Gaedigk, EM Sellers, RF Tyndale, | ||||||||
| The ability to metabolize CYP2D6 substrates sparteine, debrisoquine, and dextromethorphan was studied in healthy Caucasian (n = 20), Ghanaian (n = 21), and Chinese (n = 22) CYP2D6 extensive metabolizers. Genotype analysis for the CYP2D6*1, *3, *4, *5, *9, *10, and *17 alleles was performed. Interethnic differences in the disposition of the probe drugs were found among the extensive metabolizers; extensive metabolizer status was confirmed by phenotype and genotype analysis. The mean metabolic rate was lower for Caucasians than for Ghanaians for sparteine (P < 0.02) and for both Ghanaians and Chinese for debrisoquine (P < 0.02). Correlation comparisons resulted in lower pairwise correlation coefficients in Ghanaians compared with Chinese and Caucasians for every combination of probe substrates. In addition, in Chinese and Caucasians, metabolic rates for each pair of probe drugs were significantly correlated (P < 0.002), but in Ghanaians the dextromethorphan metabolic rates were not correlated to either sparteine or debrisoquine (P < 0.05). Even when only those with a CYP2D6*1/*1 genotype were included in the correlation calculations, the Ghanaians had very low correlation coefficients (r(s) - 0.02-0.2, n = 9); much lower than those found in Caucasian (r(s) 0.78-0.92, n = 14) or Chinese (r(s) 0.54-0.96, n = 7) individuals. Quinidine had significantly less affect on sparteine metabolic rates in Ghanaians than both Caucasians and Chinese (P < 0.02). In addition, five of the 21 Ghanaian individuals had dextromethorphan metabolic ratios which were unaffected by quinidine. These individuals also had differences in urinary recovery of dextromethorphan and its metabolites when compared to the other Ghanaian individuals. These results confirm the large ethnic differences in probe drug metabolism and quinidine sensitivity among these ethnic groups. They also suggest that the Ghanaians have an additional unidentified allele(s) with altered substrate specificity and quinidine sensitivity which is currently genotyped as CYP2D6*1. | ||||||||
| 90 | 48.09 | 15297414 | 2005.03.07 | + | + | Primary acute lymphoblastic leukemia cells use a novel promoter and 5'noncoding exon for the human reduced folate carrier that encodes a modified carrier translated from an upstream translational start. | Clin Cancer Res | |
| RM Flatley, SG Payton, JW Taub, LH Matherly, | ||||||||
| The human reduced folate carrier (hRFC) is reported to be regulated by up to seven alternatively spliced noncoding exons (A1, A2, A, B, C, D, and E). Noncoding exon and promoter usage was analyzed in RNAs from 27 childhood acute lymphoblastic leukemia (ALL) specimens by real-time PCR and/or 5' rapid amplification of cDNA ends (5' RACE) assay. By real-time PCR, total hRFC transcripts in ALL spanned a 289-fold range. Over 90% of hRFC transcripts were transcribed with A1, A2, and B 5' untranslated regions (UTRs). Analysis of 5' RACE clones showed that the A1 + A2 5'UTRs contained A1 sequence alone or a fusion of A1 and A2, implying the existence of a single, alternatively spliced 1021-bp A1/A2 noncoding region. High frequency sequence polymorphisms (AGG deletion, C/T transition) identified in the A1/A2 region by 5'RACE were confirmed in normal DNAs. By reporter assays in HepG2 hepatoma and Jurkat leukemia cells, A1/A2 promoter activity was localized to a 134-bp minimal region. Translation from an upstream AUG in the A1/A2 noncoding region in-frame with the normal translation start resulted in synthesis of a larger ( approximately 7 kDa) hRFC protein with transport properties altered from those for wild-type hRFC. Although there was no effect on transcript or protein stabilities, in vitro translation from A1/A2 transcripts was decreased compared with those with the B 5'UTR. Our results document the importance of the hRFC A1/A2 upstream region in childhood ALL and an intricate transcriptional and posttranscriptional regulation of hRFC-A1/A2 mRNAs. Furthermore, they suggest that use of the A1/A2 5'UTR may confer a transport phenotype distinct from the other 5'UTRs due to altered translation efficiency and transport properties. | ||||||||
| 91 | 48.05 | 11007777 | 2001.02.08 | + | + | Molecular cloning, expression, functional characterization, chromosomal localization, and gene structure of junctate, a novel integral calcium binding protein of sarco(endo)plasmic reticulum membrane. | J Biol Chem | |
| S Treves, G Feriotto, L Moccagatta, R Gambari, F Zorzato, | ||||||||
| Screening a cDNA library from human skeletal muscle and cardiac muscle with a cDNA probe derived from junctin led to the isolation of two groups of cDNA clones. The first group displayed a deduced amino acid sequence that is 84% identical to that of dog heart junctin, whereas the second group had a single open reading frame that encoded a polypeptide with a predicted mass of 33 kDa, whose first 78 NH(2)-terminal residues are identical to junctin whereas its COOH terminus domain is identical to aspartyl beta-hydroxylase, a member of the alpha-ketoglutarate-dependent dioxygenase family. We named the latter amino acid sequence junctate. Northern blot analysis indicates that junctate is expressed in a variety of human tissues including heart, pancreas, brain, lung, liver, kidney, and skeletal muscle. Fluorescence in situ hybridization analysis revealed that the genetic loci of junctin and junctate map to the same cytogenetic band on human chromosome 8. Analysis of intron/exon boundaries of the genomic BAC clones demonstrate that junctin, junctate, and aspartyl beta-hydroxylase result from alternative splicing of the same gene. The predicted lumenal portion of junctate is enriched in negatively charged residues and is able to bind calcium. Scatchard analysis of equilibrium (45)Ca(2+) binding in the presence of a physiological concentration of KCl demonstrate that junctate binds 21.0 mol of Ca(2+)/mol protein with a k(D) of 217 +/- 20 microm (n = 5). Tagging recombinant junctate with green fluorescent protein and expressing the chimeric polypeptide in COS-7-transfected cells indicates that junctate is located in endoplasmic reticulum membranes and that its presence increases the peak amplitude and transient calcium released by activation of surface membrane receptors coupled to InsP(3) receptor activation. Our study shows that alternative splicing of the same gene generates the following functionally distinct proteins: an enzyme (aspartyl beta-hydroxylase), a structural protein of SR (junctin), and a membrane-bound calcium binding protein (junctate). | ||||||||
| 92 | 47.95 | 12827451 | 2003.10.06 | + | + | Fanconi anemia in Tunisia: high prevalence of group A and identification of new FANCA mutations. | J Hum Genet | |
| C Bouchlaka, S Abdelhak, A Amouri, H Ben Abid, S Hadiji, M Frikha, T Ben Othman, F Amri, H Ayadi, M Hachicha, A Rebaï, A Saad, K Dellagi, | ||||||||
| Fanconi anemia (FA) is a rare autosomal recessive disease characterized by progressive pancytopenia, congenital malformations, and predisposition to acute myeloid leukemia. Fanconi anemia is genetically heterogeneous, with at least eight distinct complementation groups of FA (A, B, C, D1, D2, E, F, and G) having been defined by somatic cell fusion studies. Six genes (FANCA, FANCC, FANCD2, FANCE, FANCG, and FANCF) have been cloned. Mutations of the seventh Fanconi anemia gene, BRCA2, have been shown to lead to FAD1 and probably FAB groups. In order to characterize the molecular defects underlying FA in Tunisia, 39 families were genotyped with microsatellite markers linked to known FA gene. Haplotype analysis and homozygosity mapping assigned 43 patients belonging to 34 families to the FAA group, whereas one family was probably not linked to the FANCA gene or to any known FA genes. For patients belonging to the FAA group, screening for mutations revealed four novel mutations: two small homozygous deletions 1693delT and 1751-1754del, which occurred in exon 17 and exon 19, respectively, and two transitions, viz., 513G-->A in exon 5 and A-->G at position 166 (IVS24+166A-->G) of intron 24. Two new polymorphisms were also identified in intron 24 (IVS24-5G/A and IVS24-6C/G). | ||||||||
| 93 | 47.95 | 17112803 | 2007.01.10 | + | + | High-dose methotrexate in pediatric acute lymphoblastic leukemia: impact of ABCC2 polymorphisms on plasma concentrations. | Clin Pharmacol Ther | |
| T Rau, B Erney, R Göres, T Eschenhagen, J Beck, T Langer, | ||||||||
| OBJECTIVE: The adenosine triphosphate-binding cassette (ABC) class transporter ABCC2 (MRP2 [multidrug resistance related protein 2] or cMOAT [canalicular multispecific organic anion transporter]) is involved in the cellular outward transport and elimination of methotrexate. We hypothesized that common genetic variations may contribute to the variability of high-dose methotrexate pharmacokinetics. METHODS: Polymorphisms in all 32 exons of the ABCC2 gene were analyzed in a reference group of 59 healthy white subjects by polymerase chain reaction, single-strand conformation polymorphism, and sequencing. Subsequently, we assessed the association of polymorphisms with the methotrexate plasma concentrations in 44 pediatric patients with acute lymphoblastic leukemia (ALL) (29 male and 15 female patients; mean age, 6.8+/-4.8 years). Patients received 4 cycles of 5000 mg/m2 body surface area according to the ALL-Berlin-Frankfurt-Muenster (BFM) 95 or ALL-BFM 2000 protocol. RESULTS: In the reference group we detected 8 frequent single-nucleotide polymorphisms. Five of these were in complete linkage disequilibrium. Overall, 5 new polymorphisms are described. The genotype distribution of the patient cohort was not significantly different from the reference collective. The mean plasma methotrexate area under the curve from 36 to 48 hours after the start of the infusion was significantly 2-fold higher in female patients carrying at least 1 -24T allele as compared with all other patients (14.2+/-12.8 h.micromol/L versus 6.9+/-4.2 h.micromol/L, P<.001). The risk to have 2 or more cycles necessitating an intensification of folinate rescue was 9-fold (95% confidence interval, 1.8- to 44-fold) in female patients carrying at least 1 T allele (P=.0067). CONCLUSION: The data suggest a hitherto unknown gender-specific impact of the -24C>T ABCC2 gene polymorphism on high-dose methotrexate pharmacokinetics. Whereas a nonfunctional MRP2 variant has been described in a patient with severe impairment of methotrexate excretion, our study is the first to suggest that a frequent ABCC2 polymorphism contributes to variability of methotrexate kinetics. | ||||||||
| 94 | 47.92 | 15274053 | 2005.02.16 | + | + | Association analysis of the DRD4 and COMT genes in methamphetamine abuse. | Am J Med Genet B Neuropsychiatr Genet | |
| T Li, CK Chen, X Hu, D Ball, SK Lin, W Chen, PC Sham, el-W Loh, RM Murray, DA Collier, | ||||||||
| We analyzed two polymorphisms in genes encoding proteins of the dopamine system, the Val158Met polymorphism in the catechol-O-methyltransferase gene and the 120-bp VNTR polymorphism in the promoter of the dopamine D4 receptor gene for association with methamphetamine abuse. We used a case/control design with 416 methamphetamine abusing subjects and 435 normal controls. All subjects were Han Chinese from Taiwan. We found an excess of the high activity Val158 allele in the methamphetamine abuser group, consistent with several previous reports of association of this allele with drug abuse. The 120-bp VNTR polymorphism in the promoter of the dopamine D4 receptor gene itself did not show significant association with methamphetamine abuse. However, analysis of the 120-bp VNTR polymorphism and the exon 3 VNTR in the dopamine D4 receptor as a haplotype showed significant association with methamphetamine abuse, which gave an empirical P value 0.0034 for a heterogeneity model. Moreover, there were significant interactive effects between polymorphisms in the catechol-O-methyltransferase and dopamine D4 genes. The evidence of interaction between COMT 158 Val/Met and DRD4 48-bp VNTR polymorphisms (P = 0.0003, OR = 1.45, 95% CI: 1.148-1.77), and between COMT 158 Val/Met and DRD4 120 bp promoter polymorphisms (P = 0.01, OR = 1.10, 95% CI: 1.10-1.18) were significant but the latter was weak. We conclude that genetic variation in the dopamine system may encode an additive effect on risk of becoming a methamphetamine abuser. | ||||||||
| 95 | 47.90 | 9361025 | 1998.03.18 | + | + | Functional modeling of vitamin responsiveness in yeast: a common pyridoxine-responsive cystathionine beta-synthase mutation in homocystinuria. | Hum Mol Genet | |
| CE Kim, PM Gallagher, AB Guttormsen, H Refsum, PM Ueland, L Ose, I Folling, AS Whitehead, MY Tsai, WD Kruger, | ||||||||
| Cystathionine beta-synthase (CBS) deficiency is an autosomal recessive disorder which results in extremely elevated levels of total plasma homocysteine (tHcy) and high risk of thromboembolic events. About half of all patients diagnosed with CBS deficiency respond to pyridoxine treatment with a significant lowering of tHcy levels. We examined 12 CBS-deficient patients from 10 Norwegian families for mutations in the CBS gene and identified mutations in 18 of the 20 CBS alleles. Five of the seven patients classified as pyridoxine-responsive contain the newly identified point mutation, G797A (R266K). This point mutation is tightly linked with a previously identified 'benign' 68 bp duplication of the intron 7-exon 8 boundary within the CBS gene. We tested the effect of all of the mutations identified on human CBS function utilizing a yeast system. Five of the six mutations had a distinguishable phenotype in yeast, indicating that they were in fact pathogenic. Interestingly, the G797A allele had no phenotype when the yeast were grown in high concentrations of pyridoxine, but a severe phenotype when grown in low concentrations, thus mirroring the behavior in humans. These studies show that the G797A mutation is an important cause of pyridoxine-responsive CBS deficiency and demonstrate the utility of yeast functional assays in the analysis of human mutations. | ||||||||
| 96 | 47.88 | 12627475 | 2003.07.14 | + | + | Family-based and case-control association studies of catechol-O-methyltransferase in attention deficit hyperactivity disorder suggest genetic sexual dimorphism. | Am J Med Genet B Neuropsychiatr Genet | |
| Q Qian, Y Wang, R Zhou, J Li, B Wang, S Glatt, SV Faraone, | ||||||||
| Attention deficit hyperactivity disorder (ADHD) is the most common childhood-onset behavioral disorder. Boys are more often affected than girls. Family, twin, and adoption studies have supported a strong genetic basis. Some studies show that a catechol-O-methyltransferase (COMT) polymorphism affecting enzyme activity was associated with personality characteristics and diseases, such as novelty-seeking personality, substance abuse, and heroin addiction, whose features are similar to ADHD or are associated with ADHD. These findings suggest that the COMT gene may be a candidate gene for ADHD. TDT, HHRR, and case-control association studies were conducted within a sample of 202 nuclear ADHD families, 340 ADHD cases, and 226 controls in the Han Chinese population. Diagnoses and ADHD subtypes were ascertained according to DSM-IV criteria using American Clinical Diagnostic Interviewing Scales. The HHRR analysis suggested that the low enzyme-activity COMT Met allele was preferentially transmitted to ADHD boys (160 trios, chi(2) = 3.858, P = 0.05, df = 1) but not girls. This association is particularly pronounced among male ADHD probands without any comorbidity (50 trios, HHRR: chi(2) = 5.128, P = 0.024, df = 1; TDT: chi(2) = 4.558, P = 0.033, df = 1), especially the ADHD-I subtype (32 trios, HHRR: chi(2) = 5.792, P = 0.016, df = 1; TDT: chi(2) = 5.333, P = 0.021, df = 1). The case-control study revealed that the Val allele was more frequent in females meeting ICD-10 or DSM-IV criteria for ADHD than in female controls (86 and 79.5%, respectively, chi(2) = 4.059, P = 0.044, df = 1). Although these results suggest the COMT gene exerts some influence on the risk for ADHD in the Han Chinese population, given the potential for Type I error, these findings require replication before drawing definitive conclusions. | ||||||||
| 97 | 47.76 | 9511177 | 1998.04.21 | + | + | Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population. | Pharmacogenetics | |
| EU Griese, UM Zanger, U Brudermanns, A Gaedigk, G Mikus, K Mörike, T Stüven, M Eichelbaum, | ||||||||
| The polymorphic cytochrome P450 CYP2D6 catalyses the biotransformation of at least 40 drugs. The CYP2D6 genetic polymorphism is responsible for pronounced interindividual differences in plasma concentrations and, hence, in drug action and side-effects after administration of the same dose. Provided there is a close relationship between CYP2D6 genotypes and catalytic function, genotyping could be used in the clinical setting for individualization of drug dose. In the present study, we evaluated the relationship between the in-vivo enzyme activity and 35 different genotypes in order to determine whether genotyping can be used to predict a person's metabolic capacity for CYP2D6-catalysed drug oxidation using sparteine as a probe drug. One hundred and ninety-five Caucasian individuals were genotyped for seven nonfunctional (CYP2D6 x 3, x 4, x 5, x 6, x 7, x 8, x 16) and eight functional alleles (CYP2D6 x 1, x 2, x 2 x 2, x 2B, x 2B x 2, x 9, x 10, x 17). The metabolic ratio distribution for sparteine showed trimodality, with 15 poor metabolizers, 21 intermediate metabolizers, and 1.59 extensive and ultrarapid metabolizers. All poor metabolizers were unambiguously identified as carriers of two nonfunctional alleles. In contrast, the most frequent functional genotypes extensively overlapped and, with few exceptions, genotype was not a useful predictor of function. Gene dose effects among homozygotes and heterozygotes of the major functional alleles were not significant and could not explain the wide variations. Only a minor fraction of phenotypical ultrarapid metabolizers, arbitrarily defined as individuals with a metabolic ratio < 0.2, could be identified as carriers of three functional gene copies, including duplicated CYP2D6 x 2 x 2 alleles. Similarly, only a minor fraction of the intermediate metabolizers had predictive genotypes involving alleles coding for enzyme with impaired function. Thus, genotyping correctly identifies poor metabolizers, but quantitative prediction of drug metabolism capacity among extensive metabolizers is not possible. | ||||||||
| 98 | 47.76 | 11034254 | 2001.03.08 | + | + | Genetic polymorphism of CYP2D6 and CYP2C19 metabolism determined by phenotyping Israeli ethnic groups. | Ther Drug Monit | |
| M Britzi, M Bialer, L Arcavi, A Shachbari, T Kapitulnik, S Soback, | ||||||||
| Genetic polymorphism of the cytochrome P450 isoenzymes CYP2D6 and CYP2C19 was determined by phenotyping four ethnic groups of the Israeli population. The groups consisted of Ethiopian subjects, Yemenite subjects, and Russian subjects representing first-generation new immigrants and an Israeli Arab group. Dextromethorphan was used as the probe for CYP2D6 activity and mephenytoin was used for CYP2C19 activity. The two drugs were administered simultaneously and urine samples were collected over a period of 8 hours. The CYP2D6 phenotype was determined from the ratio of dextromethorphan conversion to dextrorphan and the CYP2C19 phenotype from the ratio of S-mephenytoin and R-mephenytoin. The used liquid chromatographic method was able to completely separate dextrorphan and dextromethorphan. Fluorescence detection allowed dextromethorphan quantification at 1 ng/mL. Mephenytoin enantiomers were completely separated in high-performance liquid chromatography and the respective fractions were collected and analyzed using a gas chromatography/mass spectrometry system with selective ion monitoring. The prevalence of poor metabolizer phenotype of dextromethorphan (CYP2D6) in the Yemenite (0%) and Ethiopian groups (0%) was significantly different from the prevalence in the Russian (17%) and Israeli Arab (9%) groups. A significant difference was also found in the distribution of the metabolic ratio of the extensive metabolizer phenotype between the Ethiopian group and the Russian and Yemenite groups. No significant difference was found in the prevalence of poor mephenytoin metabolizer phenotype (CYP2C19) between the Yemenite (8%), Ethiopian (6%), Russian (9%), and Israeli Arab (8%) groups. No difference was observed in the distribution of metabolic ratio within the extensive metabolizer phenotype subgroups of the four ethnic groups. | ||||||||
| 99 | 47.76 | 8737761 | 1997.03.18 | + | + | In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. | Eur J Clin Pharmacol | |
| C Transon, T Leemann, P Dayer, | ||||||||
| OBJECTIVE: The affinity of (+)-, (-)- and (+/-)- fluvastatin, a new synthetic HMG-CoA reductase inhibitor developed as a racemate, for specific human P450 monooxygenases in liver microsomes was compared with that of the pharmacologically active acidic forms of lovastatin, pravastatin and simvastatin. METHODS: Affinity was determined as the inhibitory potency for prototype reactions for 3 major drug metabolising enzymes: diclofenac 4'-hydroxylation (CYP2C9), dextromethorphan O-demethylation (CYP2D6), and midazolam 1'-hydroxylation (CYP3A4). RESULTS: Lovastatin acid, pravastatin and simvastatin acid displayed moderate affinity for all three P450 isozymes (estimated Ki > 50 micromol.1(-1)). Racemic and (+)- and (-)-fluvastatin showed moderate affinity (estimated Ki > 50 micromol.1(-1)) for CYP2D6 and CYP3A4, whereas their affinity for CYP2C9 was high (estimated Ki < 1 micromol.1(-1)). Diclofenac 4'-hydroxylation was competitively and stereoselectively inhibited, with measured Ki's of 0.06 and 0.28 micromol.1(-1) for (+)- and (-)- fluvastatin, respectively. CONCLUSION: Fluvastatin selectively inhibits a major drug metabolising enzyme (CYP2C9), the (+)-isomer (pharmacologically more active) showing 4-5 fold higher affinity. As already reported for lovastatin and simvastatin, in vivo drug interactions by inhibition of liver oxidation of CYP2C9 substrates (e.g. hypoglyceamic sulphonylureas and oral anticoagulants) may be expected. | ||||||||
| 100 | 47.74 | 14604448 | 2004.05.06 | + | + | Age-dependent antidepressant pharmacogenomics: polymorphisms of the serotonin transporter and G protein beta3 subunit as predictors of response to fluoxetine and nortriptyline. | Int J Neuropsychopharmacol | |
| PR Joyce, RT Mulder, SE Luty, JM McKenzie, AL Miller, GR Rogers, MA Kennedy, | ||||||||
| In 169 depressed patients randomized to treatment with either fluoxetine or nortriptyline, we examined whether polymorphisms of the serotonin transporter and the G protein beta3 subunit influenced response to these antidepressants. For depressed patients under the age of 25 yr the T allele of the G protein beta3 subunit was associated with a markedly poorer response to nortriptyline, while serotonin transporter polymorphisms did not predict antidepressant response. However, in patients 25 yr or older, the G protein beta3 polymorphisms did not predict antidepressant response, while the s,s genotype of the serotonin transporter was associated with a poorer response to both fluoxetine and nortriptyline. These differential pharmacogenetic predictors of antidepressant response by age, may provide clues to understanding the discontinuities in pharmacological responsiveness of child/adolescent and adult depressive disorders. | ||||||||
| 101 | 47.73 | 15742976 | 2005.05.11 | + | + | Metabolism of human cytochrome P450 marker substrates in mouse: a strain and gender comparison. | Xenobiotica | |
| S Löfgren, AL Hagbjörk, S Ekman, R Fransson-Steen, Y Terelius, | ||||||||
| The aim was to characterize mouse gender and strain differences in the metabolism of commonly used human cytochrome (CYP) P450 probe substrates. Thirteen human CYP probe substrates (phenacetin, coumarin, 7-ethoxy-4-trifluoromethyl coumarin, amiodarone, paclitaxel, diclofenac, S-mephenytoin, bufuralol, dextromethorphan, chlorzoxazone, p-nitrophenol, testosterone and lauric acid) were used in activity measurements. The metabolism of the probe substrates was compared in liver microsomes from male and female NMRI, CBA, C57bl/6, 129/SvJ and CD1 strains. The expression of proteins identified on Western blots with commonly available antibodies selective for specific human and rat CYP enzymes were compared in the different mouse strains. Males had higher metabolism than corresponding females for phenacetin O-deethylation (human marker for CYP1A2 activity), and a high correlation was found between phenacetin activity and immunoreactivity in Western blots produced with rat CYP1A2 antibodies. Protein detected by antibodies cross-reacting with human CYP2B6 and rat CYP2B1/2 antibodies was female specific except for the 129/SvJ strain, where it was absent in both genders. Females generally had a higher metabolism of bufuralol 1'-hydroxylation and dextromethorphan O-demethylation (human markers for CYP2D activity). Bufuralol 1'-hydroxylation correlated with a female-dominant mouse CYP, which was detected with antibodies against rat CYP2D4. p-Nitrophenol 2-hydroxylation correlated better than chlorzoxazone 6-hydroxylation with the protein detected with antibodies against rat CYP2E1, indicating that p-nitrophenol is a more specific substrate for mouse CYP2E1. | ||||||||
| 102 | 47.69 | 8873687 | 1996.11.27 | + | + | Differences between white subjects and Chinese subjects in the in vivo inhibition of cytochrome P450s 2C19, 2D6, and 3A by omeprazole. | Clin Pharmacol Ther | |
| Y Caraco, GR Wilkinson, AJ Wood, | ||||||||
| OBJECTIVES: To determine the effects of omeprazole on indexes of CYP2D6, CYP2C19 and 3A in vivo activity and to compare these in white subjects and Chinese subjects. METHODS: Omeprazole, 40 mg/day, or placebo were administered in a double-blind crossover study for 3 weeks to eight healthy white and seven Chinese male extensive metabolizers of mephenytoin and debrisoquin. Debrisoquin (10 mg), dapsone (100 mg), and mephenytoin (100 mg) were given 1 week before administration, on the last day of administration, and 3 weeks after administration, and urine was collected over 8 hours. Phenotypic trait values were obtained from the urinary recoveries of the probe drugs or their metabolites. RESULTS: In the white subjects, omeprazole significantly inhibited CYP2C19-mediated S-mephenytoin metabolism as indicated by decreases in the urinary R/S enantiomeric ratio (63% +/- 13%; p < 0.02; mean +/- SD) and the excretion of 4'-hydroxymephenytoin (39% +/- 13%; p < 0.001). Similar but smaller changes were also noted in Chinese subjects, 22% +/- 25% (p = 0.08) and 29% +/- 13% (p < 0.002), respectively. The interracial differences in the extent of inhibition of metabolism were statistically significant (p < 0.01 and p < 0.05, respectively). In contrast, the debrisoquin urinary metabolic ratio, a measure of CYP2D6, was unaffected. The excretion of hydroxylamine dapsone-a putative probe of CYP3A activity-was reduced by 40% +/- 30% (p < 0.03) in white subjects but not in Chinese subjects. CONCLUSIONS: Omeprazole selectively inhibits the in vivo metabolism of S-mephenytoin, consistent with the predictions based on in vitro studies. The extent of interaction is greater in subjects of white European ancestry. It is to be expected that similar situations would also occur when omeprazole is coadministered with other substrates of CYP2C19. | ||||||||
| 103 | 47.62 | 15709193 | 2005.05.31 | + | + | UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. | Clin Cancer Res | |
| LE Carlini, NJ Meropol, J Bever, ML Andria, T Hill, P Gold, A Rogatko, H Wang, RL Blanchard, | ||||||||
| PURPOSE: Capecitabine and irinotecan are commonly used in the treatment of metastatic colorectal cancer (CRC). We hypothesized that germline polymorphisms within genes related to drug target (thymidylate synthase) or metabolizing enzymes (UDP-glucuronosyltransferase, UGT) would impact response and toxicity to the combination of capecitabine plus irinotecan (CPT-11). EXPERIMENTAL DESIGN: Sixty-seven patients with measurable CRC were treated with irinotecan i.v. (100 or 125 mg/m(2)) on days 1 and 8 and capecitabine orally (900 or 1,000 mg/m(2), twice daily) on days 2 through 15 of each 3-week cycle. Genomic DNA was extracted from peripheral blood and genotyped using Pyrosequencing, GeneScan, and direct sequencing (Big Dye terminator) technologies. RESULTS: The overall objective response rate was 45% with 21 patients (31%) exhibiting grade 3 or 4 diarrhea and 3 patients (4.5%) demonstrating grade 3 or 4 neutropenia in the first two cycles. Low enzyme activity UGT1A7 genotypes, UGT1A7*2/*2 (six patients) and UGT1A7*3/*3 (seven patients), were significantly associated with antitumor response (p = 0.013) and lack of severe gastrointestinal toxicity (p = 0.003). In addition, the UGT1A9 -118 (dT)(9/9) genotype was significantly associated with reduced toxicity (p = 0.002) and increased response (p = 0.047). There were no statistically significant associations between UGT1A1, UGT1A6, or thymidylate synthase genotypes and toxicity or tumor response. CONCLUSIONS: These data strongly suggest that UGT1A7 and/or UGT1A9 genotypes may be predictors of response and toxicity in CRC patients treated with capecitabine plus irinotecan. Specifically, patients with genotypes conferring low UGT1A7 activity and/or the UGT1A9 (dT)(9/9) genotype may be particularly likely to exhibit greater antitumor response with little toxicity. | ||||||||
| 104 | 47.52 | 10471065 | 1999.10.14 | + | + | Polymorphisms in NAT2, CYP2D6, CYP2C19 and GSTP1 and their association with prostate cancer. | Pharmacogenetics | |
| M Wadelius, JL Autrup, MJ Stubbins, SO Andersson, JE Johansson, C Wadelius, CR Wolf, H Autrup, A Rane, | ||||||||
| The development of prostate cancer is dependent on heredity, androgenic influences, and exposure to environmental agents. A high intake of dietary fat is associated with an increased risk of prostate cancer, either through influence on steroid hormone profiles or through production of carcinogenic compounds that require biotransformation by enzymes. The polymorphic glutathione S-transferase (GST), N-acetyltransferase (NAT), and cytochrome P450 (CYP) enzymes are of particular interest in prostate cancer susceptibility because of their ability to metabolize both endogenous and exogenous compounds, including dietary constituents. Association between different NAT2, CYP2D6, CYP2C19 and GSTP1 genotypes and prostate cancer was studied in a Swedish and Danish case-control study comprising 850 individuals. The combined Swedish and Danish study population was analysed by polymerase chain reaction for the NAT2 alleles *4, *5A, *5B, *5C, *6 and *7, and for the CYP2D6 alleles *l, *3 and *4. The Swedish subjects were also analysed for the CYP2C19 alleles *1 and *2, and the GSTP1 alleles *A, *B and *C. No association was found between prostate cancer and polymorphisms in NAT2, CYP2D6, CYP2C19 or GSTP1. An association between CYP2D6 poor metabolism and prostate cancer was seen among smoking Danes; odds ratio 3.10 (95% confidence interval 1.07; 8.93), P = 0.03, but not among smoking Swedes; odds ratio 1.19 (95% confidence interval 0.41; 3.42), P = 0.75. Smoking is not a known risk factor for prostate cancer, and the association between CYP2D6 poor metabolism and prostate cancer in Danish smokers may have arisen by chance. | ||||||||
| 105 | 47.50 | 14586384 | 2003.11.21 | + | + | Combined phenotypic assessment of cytochrome p450 1A2, 2C9, 2C19, 2D6, and 3A, N-acetyltransferase-2, and xanthine oxidase activities with the "Cooperstown 5+1 cocktail". | Clin Pharmacol Ther | |
| S Chainuvati, AN Nafziger, JS Leeder, A Gaedigk, GL Kearns, E Sellers, Y Zhang, AD Kashuba, E Rowland, JS Bertino, | ||||||||
| Previously, we have validated a 4-drug phenotyping cocktail, the "Cooperstown cocktail," using caffeine (cytochrome p450 [CYP] 1A2, N-acetyltransferase-2 [NAT2], and xanthine oxidase [XO]), dextromethorphan (CYP2D6), omeprazole (CYP2C19), and intravenous midazolam (hepatic CYP3A). Data suggest that warfarin can be used as a safe and accurate biomarker for CYP2C9, and if warfarin is administered with vitamin K, the pharmacodynamic effect is ablated. Twelve subjects received the Cooperstown cocktail, warfarin plus vitamin K, and both sets of biomarkers (Cooperstown 5+1 cocktail) in a randomized crossover fashion. On the basis of log-transformed data and a paired t test, no significant difference was seen for S-warfarin area under the serum concentration-time curve from time 0 to infinity (P =.09), omeprazole metabolic ratio (P =.374), caffeine metabolic ratio (P =.169 for CYP1A2 activity), midazolam plasma clearance (P =.573), or dextromethorphan metabolic ratio (P =.747) with the Cooperstown cocktail, warfarin plus vitamin K alone, or the Cooperstown 5+1 cocktail. During drug administration, the only side effect was mild and short-lived sedation after intravenous midazolam administration. Phenotypic measurements were in concordance with the subject's CYP2C9, CYP2C19, and CYP2D6 genotypes. The Cooperstown 5+1 cocktail may be used to simultaneously assess the activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A, NAT2, and XO. | ||||||||
| 106 | 47.41 | 17558305 | 2007.08.20 | + | + | Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese: roles of UGT1A1*6 and *28. | Pharmacogenet Genomics | |
| H Minami, K Sai, M Saeki, Y Saito, S Ozawa, K Suzuki, N Kaniwa, J Sawada, T Hamaguchi, N Yamamoto, K Shirao, Y Yamada, H Ohmatsu, K Kubota, T Yoshida, A Ohtsu, N Saijo, | ||||||||
| OBJECTIVES: SN-38, an active metabolite of irinotecan, is detoxified by glucuronidation with UGT1A isoforms, 1A1, 1A7, 1A9, and 1A10. The pharmacogenetic information on UGT1A haplotypes covering all these isoforms is important for the individualized therapy of irinotecan. Associations between UGT1A haplotypes and pharmacokinetics/pharmacodynamics of irinotecan were investigated to identify pharmacogenetic markers. METHODS: Associations between UGT1A haplotypes and the area under concentration curve ratio (SN-38 glucuronide/SN-38) or toxicities were analyzed in 177 Japanese cancer patients treated with irinotecan as a single agent or in combination chemotherapy. For association analysis, diplotypes of UGT1A gene segments [(1A1, 1A7, 1A9, 1A10), and Block C (common exons 2-5)] and combinatorial haplotypes (1A9-1A7-1A1) were used. The relationship between diplotypes and toxicities was investigated in 55 patients treated with irinotecan as a single agent. RESULTS: Among diplotypes of UGT1A genes, patients with the haplotypes harboring UGT1A1*6 or *28 had significantly reduced area under concentration curve ratios, with the effects of UGT1A1*6 or *28 being of a similar scale. A gene dose effect on the area under concentration curve ratio was observed for the number of haplotypes containing *28 or *6 (5.55, 3.62, and 2.07 for 0, 1, and 2 haplotypes, respectively, P<0.0001). In multivariate analysis, the homozygotes and double heterozygotes of *6 and *28 (*6/*6, *28/*28 and *6/*28) were significantly associated with severe neutropenia in 53 patients who received irinotecan monotherapy. CONCLUSIONS: The haplotypes significantly associated with reduced area under concentration curve ratios and neutropenia contained UGT1A1*6 or *28, and both of them should be genotyped before irinotecan is given to Japanese and probably other Asian patients. | ||||||||
| 107 | 47.29 | 17470528 | 2007.11.02 | + | + | Substrate-dependent drug-drug interactions between gemfibrozil, fluvastatin and other organic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3. | Drug Metab Dispos | |
| J Noé, R Portmann, ME Brun, C Funk, | ||||||||
| Hepatic uptake carriers of the organic anion-transporting peptide (OATP) family of solute carriers are more and more recognized as being involved in hepatic elimination of many drugs and potentially associated drug-drug interactions. The gemfibrozil-statin interaction was studied at the level of active hepatic uptake as a model for such drug-drug interactions. Active, temperature-dependent uptake of fluvastatin into primary human hepatocytes was shown. Multiple transporters are involved in this uptake as Chinese hamster ovary or HEK293 cells expressing either OATP1B1 (K(m) = 1.4-3.5 microM), OATP2B1 (K(m) = 0.7-0.8 microM), or OATP1B3 showed significant fluvastatin uptake relative to control cells. For OATP1B1 the inhibition by gemfibrozil was substrate-dependent as the transport of fluvastatin (IC(50) of 63 microM), pravastatin, simvastatin, and taurocholate was inhibited by gemfibrozil, whereas the transport of estrone-3-sulfate and troglitazone sulfate (both used at 3 microM) was not affected. The OATP1B1- but not OATP2B1-mediated transport of estrone-3-sulfate displayed biphasic saturation kinetics, with two distinct affinity components for estrone-3-sulfate (0.23 and 45 microM). Only the high-affinity component was inhibited by gemfibrozil. Recombinant OATP1B1-, OATP2B1-, and OATP1B3-mediated fluvastatin transport was inhibited to 97, 70, and 62% by gemfibrozil (200 microM), respectively, whereas only a small inhibitory effect by gemfibrozil (200 microM) on fluvastatin uptake into primary human hepatocytes was observed (27% inhibition). The results indicate that the in vitro engineered systems can not always predict the behavior in more complex systems such as freshly isolated primary hepatocytes. Therefore, selection of substrate, substrate concentration, and in vitro transport system are critical for the conduct of in vitro interaction studies involving individual liver OATP carriers. | ||||||||
| 108 | 47.25 | 8528270 | 1996.01.31 | + | + | Comparison of substrate metabolism by wild type CYP2D6 protein and a variant containing methionine, not valine, at position 374. | Pharmacogenetics | |
| CL Crespi, DT Steimel, BW Penman, KR Korzekwa, P Fernandez-Salguero, JT Buters, HV Gelboin, FJ Gonzalez, JR Idle, AK Daly, | ||||||||
| We have analysed kinetic parameters of cDNA-derived CYP2D6 proteins derived from the original CYP2D6 cDNA isolate (Gonzalez FJ et al. Nature 1988: 331, 442-446) which contains methionine at position 374 (CYP2D6-Met) and a modified cDNA which contains valine at position 374 (CYP2D6-Val). This latter protein is predicted from the CYP2D6 genomic sequence. Several quantitative differences, but no qualitative differences in metabolism were observed. CYP2D6-Met was found to have a two-fold lower Km and a three-fold lower turnover rate for (R)(+)-bufuralol 1'-hydroxylation as compared to CYP2D6-Val. In contrast, CYP2D6-Met and CYP2D6-Val had a similar Km for debrisoquine 4-hydroxylation while CYP2D6-Val had an 18-fold higher turnover rate. CYP2D6-Val and CYP2D6-Met had similar Kms for metoprolol but CYP2D6-Val showed a three-fold higher capacity for the O-demethylation reaction compared to alpha-hydroxylation which is more similar to that seen in human liver. In the case of sparteine, CYP2D6-Val and CYP2D6-Met showed similar capacities for formation of the 2-dehydrosparteine metabolite but the Km value for CYP2D6-Met was six-fold higher than that for CYP2D6-Val. Kinetic differences between CYP2D6-Met and CYP2D6-Val were further probed by examination of apparent Ki for inhibition of (R,S)(+/-)-bufuralol 1'-hydroxylation. Similar Ki values (within a factor of three) were observed for perhexiline and (R,S)-propranolol while quinidine and dextromethorphan were 8.5-fold and 21-fold more effective inhibitors of CYP2D6-Val relative to CYP2D6-Met. An allele specific polymerase chain reaction assay was developed for the CYP2D6-Met allele. The CYP2D6-Met allele was not found among 83 individuals. In the aggregate, these data indicated that the CYP2D6-Val allele is the more common allele in human populations. The quantitative kinetic differences between these two enzymes appears most pronounced for substrates/inhibitors with rigid structures. CYP2D6-Val more often has a substantially lower Km and/or a substantially higher capacity to metabolize those substrates. | ||||||||
| 109 | 47.23 | 15389755 | 2005.05.12 | + | + | DAT1, DRD4, and DRD5 polymorphisms are not associated with ADHD in Dutch families. | Am J Med Genet B Neuropsychiatr Genet | |
| SC Bakker, EM van der Meulen, N Oteman, H Schelleman, PL Pearson, JK Buitelaar, RJ Sinke, | ||||||||
| Recent meta-analyses have indicated that the dopamine transporter gene (DAT1) and the dopamine receptor genes D4 (DRD4) and D5 (DRD5) are associated with attention-deficit hyperactivity disorder (ADHD), although single studies frequently failed to show significant association. In a family-based sample of 236 Dutch children with ADHD, we have investigated the previously described variable number of tandem repeat (VNTR) polymorphisms and two additional microsatellites at the DAT1 and DRD4 loci. DRD5 was investigated using the microsatellite that was previously found to be associated. Transmission disequilibrium tests (TDTs) did not show preferential transmission of alleles or two-marker haplotypes to affected offspring. These data suggest that DAT1, DRD4, and DRD5 do not contribute substantially to ADHD in the Dutch population. | ||||||||
| 110 | 47.22 | 11410508 | 2001.09.20 | + | + | Nucleotide substitution in the ectodomain of trail receptor DR4 is associated with lung cancer and head and neck cancer. | Clin Cancer Res | |
| MJ Fisher, AK Virmani, L Wu, R Aplenc, JC Harper, SM Powell, TR Rebbeck, D Sidransky, AF Gazdar, WS El-Deiry, | ||||||||
| Allelic loss of chromosome 8p21-22 occurs frequently in cancer, including lung and head and neck squamous cell cancer. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors, including proapoptotic DR4 and KILLER/DR5, are located on 8p21-22. TRAIL receptors are candidate tumor suppressor genes, because their inactivation would be expected to result in deficient apoptotic signaling. To investigate the involvement of DR4 in human cancer, we have determined the genomic structure of DR4 and screened 31 lung cancer cell lines [14 small cell lung cancer and 17 non-small cell lung cancer (NSCLC)], many with deletions at 8p21-22, and 21 primary NSCLC samples for mutations in DR4. We found two missense alterations in the ectodomain of DR4. One, at nucleotide 626, changes a cytosine to a guanine (C626G) and results in a substitution of an arginine for threonine. The other, at nucleotide 422, changes a guanine to adenine (G422A) and results in a substitution of a histidine for arginine. Using genomic DNA sequencing and RFLP analysis, we show that these two alterations cosegregated in 96% of all of the samples (n = 243) evaluated (tumor and normal). The frequency of being homozygous for both altered alleles was 35% in the lung cancer cell lines but only 13% in age- and race-matched controls, which was a significant increase (chi(2) = 5.2, P = 0.023). The frequency of homozygosity for both alleles was also significantly increased in the primary NSCLC samples (chi(2) = 9.2, P = 0.002) as compared with the age- and race-matched controls. To determine whether the altered alleles are specific for lung cancer, we evaluated 19 head and neck squamous cell cancer and 25 gastric adenocarcinoma samples. Forty-seven % of the former and 44% of the latter were homozygous for both the C626G and G422A alterations, and this was significantly elevated relative to age- and race-matched controls (chi(2) = 8.6, P = 0.003 and chi(2) = 8.2, P = 0.004). These alterations result in amino acid changes in or near the ligand-binding domain of DR4 and, based on the crystal structure of DR5 and its homology with DR4, have the potential to affect TRAIL binding to DR4. Our results suggest that the altered DR4 alleles may be associated with, and should be investigated additionally as potential markers for, predisposition to common malignancies. | ||||||||
| 111 | 47.20 | 16115929 | 2005.12.21 | + | + | Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas. | Clin Cancer Res | |
| M Taron, Y Ichinose, R Rosell, T Mok, B Massuti, L Zamora, JL Mate, C Manegold, M Ono, C Queralt, T Jahan, JJ Sanchez, M Sanchez-Ronco, V Hsue, D Jablons, JM Sanchez, T Moran, | ||||||||
| PURPOSE: Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) confer a strong sensitivity to gefitinib, a selective tyrosine kinase inhibitor of EGFR. EXPERIMENTAL DESIGN: We examined EGFR mutations at exons 18, 19, and 21 in tumor tissue from 68 gefitinib-treated, chemorefractory, advanced non-small cell lung cancer patients from the United States, Europe, and Asia and in a highly gefitinib-sensitive non-small cell lung cancer cell line and correlated their presence with response and survival. In addition, in a subgroup of 28 patients for whom the remaining tumor tissue was available, we examined the relationship among EGFR mutations, CA repeats in intron 1 of EGFR, EGFR and caveolin-1 mRNA levels, and increased EGFR gene copy numbers. RESULTS: Seventeen patients had EGFR mutations, all of which were in lung adenocarcinomas. Radiographic response was observed in 16 of 17 (94.1%) patients harboring EGFR mutations, in contrast with 6 of 51 (12.6%) with wild-type EGFR (P < 0.0001). Probability of response increased significantly in never smokers, patients receiving a greater number of prior chemotherapy regimens, Asians, and younger patients. Median survival was not reached for patients with EGFR mutations and was 9.9 months for those with wild-type EGFR (P = 0.001). EGFR mutations tended to be associated with increased numbers of CA repeats and increased EGFR gene copy numbers but not with EGFR and caveolin-1 mRNA overexpression (P = not significant). CONCLUSIONS: The presence of EGFR mutations is a major determinant of gefitinib response, and targeting EGFR should be considered in preference to chemotherapy as first-line treatment in lung adenocarcinomas that have demonstrable EGFR mutations. | ||||||||
| 112 | 47.16 | 17558304 | 2007.08.20 | + | + | A pharmacogenomics study of the human estrogen glucuronosyltransferase UGT1A3. | Pharmacogenet Genomics | |
| B Caillier, J Lépine, J Tojcic, V Ménard, L Perusse, A Bélanger, O Barbier, C Guillemette, | ||||||||
| UGT1A3 is one of the most efficient at conjugating estrone, a precursor for biosynthesis of estradiol in peripheral tissues. We established the genetic mechanisms that might contribute to individual variation in UGT1A3 expression and activity. UGT1A3 first exon and 5'-flanking regions were sequenced in 249 Caucasians. We identified 17 polymorphisms, among them seven regulatory and 10 exonic polymorphisms with six leading to amino-acid changes. Luciferase reporter assays, site-directed mutagenesis and electrophoretic mobility shift assays using hepatoma HepG2 cells were carried out to show functionality of variant promoters. Reduced transcriptional activity was associated with all six variant promoters (two-fold; P<0.001). One of the potential mechanisms would involve the -148 T>C and -581 C>T variations that modulate gene function by affecting hepatocyte nuclear factor-1alpha and hepatocyte nuclear factor-4alpha binding, respectively. Then, estrone-conjugating activity was assessed with 11 heterologously expressed allozymes. Three phenotypes were observed; UGT1A3*1, *2 (WR, VA) and *3 (WR) with high intrinsic clearance values; UGT1A3*5 (QR, WR), *7 (FI), *9 (WR, ML), *10 (VA) and *11 (WR, VA and MI) had intermediate CLint (2X-10X lower vs. *1), whereas UGT1A3*4 (RW), *6 (WR, VA, MV) and *8 (AV) had low CLint (>10X lower vs. *1). Diplotype analyses indicate that 20.1% of individuals carry two alleles affecting UGT1A3 expression and/or activity. This study did not investigate genotype-phenotype association, but raise the possibility that genetically determined variation might contribute to variability in the inactivation of estrone by UGT1A3 and subsequent changes in lifetime exposure to estrogens potentially modifying risk of cancer. | ||||||||
| 113 | 47.13 | 7604000 | 1995.08.10 | + | + | The human plakoglobin gene localizes on chromosome 17q21 and is subjected to loss of heterozygosity in breast and ovarian cancers. | Proc Natl Acad Sci U S A | |
| H Aberle, C Bierkamp, D Torchard, O Serova, T Wagner, E Natt, J Wirsching, C Heidkämper, M Montagna, HT Lynch, | ||||||||
| The gene encoding human plakoglobin was mapped to chromosome 17q12-q22. An intragenic restriction fragment length polymorphism was used to localize the plakoglobin gene distal to locus KRT10 and proximal to the marker D17S858. The plakoglobin gene colocalizes with the polymorphic 17q21 marker UM8 on the same cosmid insert. This subregion of chromosome 17 is known to be particularly subjected to genetic alterations in sporadic breast and ovarian tumors. We show loss of heterozygosity of the plakoglobin gene in breast and ovarian tumors. We have identified a low-frequency polymorphism in the plakoglobin coding sequence which results in an arginine to histidine substitution at amino acid position 142 of the protein, as well as a silent mutation at nucleotide position 332 of the coding sequence. This polymorphism allowed us to demonstrate an allelic association of plakoglobin with predisposition to familial breast and ovarian cancers. Our results, together with the present knowledge about the biological function of plakoglobin, suggest that plakoglobin might represent a putative tumor suppressor gene for breast and ovarian cancers. | ||||||||
| 114 | 47.02 | 10215754 | 1999.06.11 | + | + | Metabolic interactions between mibefradil and HMG-CoA reductase inhibitors: an in vitro investigation with human liver preparations. | Br J Clin Pharmacol | |
| T Prueksaritanont, B Ma, C Tang, Y Meng, C Assang, P Lu, PJ Reider, JH Lin, TA Baillie, | ||||||||
| AIMS: To determine the effects of mibefradil on the nletabolism in human liver microsomal preparations of the HMG-CoA reductase inhibitors simvastatin, lovastatin, atorvastatin, cerivastatin and fluvastatin. METHODS: Metabolism of the above five statins (0.5, 5 or 10 microM), as well as of specific CYP3A4/5 and CYP2C8/9 marker substrates, was examined in human liver microsomal preparations in the presence and absence of mibefradil (0.1-50 microM). RESULTS: Mibefradil inhibited, in a concentration-dependent fashion, the metabolism of the four statins (simvastatin, lovastatin, atorvastatin and cerivastatin) known to be substrates for CYP3A. The potency of inhibition was such that the IC50 values (<1 microM) for inhibition of all of the CYP3A substrates fell within the therapeutic plasma concentrations of mibefradil, and was comparable with that of ketoconazole. However, the inhibition by mibefradil, unlike that of ketoconazole, was at least in part mechanism-based. Based on the kinetics of its inhibition of hepatic testosterone 6beta-hydroxylase activity, mibefradil was judged to be a powerful mechanism-based inhibitor of CYP3A4/5, with values for Kinactivation, Ki and partition ratio (moles of mibefradil metabolized per moles of enzyme inactivated) of 0.4 min(-1), 2.3 microM and 1.7, respectively. In contrast to the results with substrates of CYP3A, metabolism of fluvastatin, a substrate of CYP2C8/9, and the hydroxylation of tolbutamide, a functional probe for CYP2C8/9, were not inhibited by mibefradil. CONCLUSION: Mibefradil, at therapeutically relevant concentrations, strongly suppressed the metabolism in human liver microsomes of simvastatin, lovastatin, atorvastatin and cerivastatin through its inhibitory effects on CYP3A4/5, while the effects of mibefradil on fluvastatin, a substrate for CYP2C8/9, were minimal in this system. Since mibefradil is a potent mechanism-based inhibitor of CYP3A4/5, it is anticipated that clinically significant drug-drug interactions will likely ensue when mibefradil is coadministered with agents which are cleared primarily by CYP3A-mediated pathways. | ||||||||
| 115 | 46.95 | 10619354 | 2000.01.31 | + | + | Single nucleotide polymorphisms (SNPs) in the estrogen receptor gene and breast cancer susceptibility. | J Steroid Biochem Mol Biol | |
| EL Schubert, MK Lee, B Newman, MC King, | ||||||||
| In order to evaluate the role of inherited variation in the estrogen receptor (ESR1) gene in human breast cancer, we determined intronic sequences flanking each ESRI exon; identified multiple SNPs and length polymorphisms in the ESR1 coding sequence, splice junctions and regulatory regions; and genotyped families at high risk of breast cancer and population-based breast cancer patients and controls. Of 10 polymorphic sites in ESR1, four are synonymous SNPs, two are nonsynonymous SNPs and four are length polymorphisms; five are novel. No ESR1 polymorphisms were associated with breast cancer, either in the high-risk families or the case-control study. We therefore conclude that inherited genetic variation is not a mechanism by which the estrogen receptor is commonly involved in breast cancer development. | ||||||||
| 116 | 46.95 | 12563178 | 2003.09.25 | + | + | Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients. | Pharmacogenetics | |
| B Chowbay, S Cumaraswamy, YB Cheung, Q Zhou, EJ Lee, | ||||||||
| Intestinal cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) both play a vital role in the metabolism of oral cyclosporine (CsA). We investigated the genetic polymorphisms in CYP3A4(promoter region and exons 5, 7 and 9) and MDR1 (exons 12, 21 and 26) genes and the impact of these polymorphisms on the pharmacokinetics of oral CsA in stable heart transplant patients (n = 14). CYP3A4 polymorphisms were rare in the Asian population and transplant patients. Haplotype analysis revealed 12 haplotypes in the Chinese, eight in the Malays and 10 in the Indians. T-T-T was the most common haplotype in all ethnic groups. The frequency of the homozygous mutant genotype at all three loci (TT-TT-TT) was highest in the Indians (31%) compared to 19% and 15% in the Chinese and Malays, respectively. In heart transplant patients, CsA exposure (AUC(0-4 h), AUC(0-12 h) and C(max)) was high in patients with the T-T-T haplotypes compared to those with C-G-C haplotypes. These findings suggest that haplotypes rather than genotypes influence CsA disposition in transplant patients. | ||||||||
| 117 | 46.92 | 17470523 | 2007.11.02 | + | + | Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17. | Drug Metab Dispos | |
| H Shen, MM He, H Liu, SA Wrighton, L Wang, B Guo, C Li, | ||||||||
| Polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene are a major cause of pharmacokinetic variability in human. Although the poor metabolizer phenotype is known to be caused by two null alleles leading to absence of functional CYP2D6 protein, the large variability among individuals with functional alleles remains mostly unexplained. Thus, the goal of this study was to examine the intrinsic enzymatic differences that exist among the several active CYP2D6 allelic variants. The relative catalytic activities (enzyme kinetics) of three functionally active human CYP2D6 allelic variants, CYP2D6.1, CYP2D6.10, and CYP2D6.17, were systematically investigated for their ability to metabolize a structurally diverse set of clinically important CYP2D6-metabolized drugs [atomoxetine, bufuralol, codeine, debrisoquine, dextromethorphan, (S)-fluoxetine, nortriptyline, and tramadol] and the effects of various CYP2D6-inhibitors [cocaine, (S)-fluoxetine, (S)-norfluoxetine, imipramine, quinidine, and thioridazine] on these three variants. The most significant difference observed was a consistent but substrate-dependent decease in the catalytic efficiencies of cDNA-expressed CYP2D6.10 and CYP2D6.17 compared with CYP2D6.1, yielding 1.32 to 27.9 and 7.33 to 80.4% of the efficiency of CYP2D6.1, respectively. The most important finding from this study is that there are mixed effects on the functionally reduced allelic variants in enzyme-substrate affinity or enzyme-inhibitor affinity, which is lower, higher, or comparable to that for CYP2D6.1. Considering the rather high frequencies of CYP2D6*10 and CYP2D6*17 alleles for Asians and African Americans, respectively, these data provide further insight into ethnic differences in CYP2D6-mediated drug metabolism. However, as with all in vitro to in vivo extrapolations, caution should be applied to the clinical consequences. | ||||||||
| 118 | 46.92 | 8528266 | 1996.01.31 | + | + | Identification of an NAD(P)H:quinone oxidoreductase polymorphism and its association with lung cancer and smoking. | Pharmacogenetics | |
| EA Rosvold, KA McGlynn, ED Lustbader, KH Buetow, | ||||||||
| The enzyme NAD(P)H:quinone oxidoreductase (NQO1) catalyses bioreduction and bioactivation reactions. A mutation in the NQO1 gene had previously been demonstrated in a cancer cell line with reduced NQO1 activity. In this study, several regions of the NQO1 locus were examined for constitutional variation at the DNA level. The previously described mutation in exon 6 was detected by the single-strand conformation polymorphism technique. This was confirmed by sequencing to result from a C-->T substitution. Genotype analysis in the Centre d'Etude Polymorphisme Humain (CEPH) reference panel revealed two alleles with frequencies of 0.87 and 0.13 and demonstrated Mendelian transmission. Genotype distributions were consistent with Hardy-Weinberg equilibrium. Linkage analysis mapped the gene locus to chromosome 16q. NQO1 was felt to be a candidate gene for the susceptibility to lung cancer, given its potential role in protection against carcinogenic compounds. The frequency of NQO1 variants was examined in 150 lung cancer cases and in two reference populations. The allele distribution in CEPH parent controls was significantly different from cases (chi 2 = 5.52, p = 0.019), but no difference was noted between cases and a healthy local reference population. When the local reference distribution was stratified on smoking status, a significant difference was observed (chi 2 = 3.88, p = 0.048).(ABSTRACT TRUNCATED AT 250 WORDS) | ||||||||
| 119 | 46.89 | 10759690 | 2000.06.21 | + | + | In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6. | Br J Clin Pharmacol | |
| JW Ko, Z Desta, NV Soukhova, T Tracy, DA Flockhart, | ||||||||
| AIMS: To examine the potency of ticlopidine (TCL) as an inhibitor of cytochrome P450s (CYP450s) in vitro using human liver microsomes (HLMs) and recombinant human CYP450s. METHODS: Isoform-specific substrate probes of CYP1A2, 2C19, 2C9, 2D6, 2E1 and 3A4 were incubated in HLMs or recombinant CYPs with or without TCL. Preliminary data were generated to simulate an appropriate range of substrate and inhibitor concentrations to construct Dixon plots. In order to estimate accurately inhibition constants (Ki values) of TCL and determine the type of inhibition, data from experiments with three different HLMs for each isoform were fitted to relevant nonlinear regression enzyme inhibition models by WinNonlin. RESULTS: TCL was a potent, competitive inhibitor of CYP2C19 (Ki = 1.2 +/- 0.5 microM) and of CYP2D6 (Ki = 3.4 +/- 0.3 microM). These Ki values fell within the therapeutic steady-state plasma concentrations of TCL (1-3 microM). TCL was also a moderate inhibitor of CYP1A2 (Ki = 49 +/- 19 microM) and a weak inhibitor of CYP2C9 (Ki > 75 microM), but its effect on the activities of CYP2E1 (Ki = 584 +/- 48 microM) and CYP3A (> 1000 microM) was marginal. CONCLUSIONS: TCL appears to be a broad-spectrum inhibitor of the CYP isoforms, but clinically significant adverse drug interactions are most likely with drugs that are substrates of CYP2C19 or CYP2D6. | ||||||||
| 120 | 46.89 | 11927841 | 2002.09.03 | + | + | Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. | Pharmacogenetics | |
| CR Lee, JA Goldstein, JA Pieper, | ||||||||
| The discovery of six distinct polymorphisms in the genetic sequence encoding for the cytochrome P450 2C9 (CYP2C9) protein has stimulated numerous investigations in an attempt to characterize their population distribution and metabolic activity. Since the CYP2C9*1, *2 and *3 alleles were discovered first, they have undergone more thorough investigation than the recently identified *4, *5 and *6 alleles. Population distribution data suggest that the variant *2 and *3 alleles are present in approximately 35% of Caucasian individuals; however, these alleles are significantly less prevalent in African-American and Asian populations. In-vitro data have consistently demonstrated that the CYP2C9*2 and *3 alleles are associated with significant reductions in intrinsic clearance of a variety of 2C9 substrates compared with CYP2C9*1; however, the degree of these reductions appear to be highly substrate-dependent. In addition, multiple in-vivo investigations and clinical case reports have associated genotypes expressing the CYP2C9*2 and *3 alleles with significant reductions in both the metabolism and daily dose requirements of selected CYP2C9 substrates. Individuals expressing these variant genotypes also appear to be significantly more susceptible to adverse events with the narrow therapeutic index agents warfarin and phenytoin, particularly during the initiation of therapy. These findings have subsequently raised numerous questions regarding the potential clinical utility of genotyping for CYP2C9 prior to initiation of therapy with these agents. However, further clinical investigations evaluating the metabolic consequences in individuals expressing the CYP2C9*2, *3, *4, *5, or *6 alleles are required before large-scale clinical genotyping can be recommended. | ||||||||
| 121 | 46.89 | 15970668 | 2006.04.20 | + | + | Chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the ABCG2 (BCRP) and ABCB1 (MDR1) drug transport pumps. | Cancer Biol Ther | |
| H Burger, H van Tol, M Brok, EA Wiemer, EA de Bruijn, G Guetens, G de Boeck, A Sparreboom, J Verweij, K Nooter, | ||||||||
| Imatinib mesylate is a selective tyrosine kinase inhibitor that is successfully used in the treatment of Philadelphia-positive chronic and acute leukaemia's, and gastrointestinal stromal tumors. We investigated whether the intended chronic oral administration of imatinib might lead to the induction of the intestinal ABC transport proteins ABCB1, ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2. Using Caco2 cells as an in vitro model for intestinal drug transport, we found that continuous exposure (up to 100 days) with imatinib (10 microM) specifically upregulates the expression of ABCG2 (maximal approximately 17-fold) and ABCB1 (maximal approximately 5-fold). The induction of gene expression appeared to be biphasic in time, with a significant increase in ABCG2 and ABCB1 at day 3 and day 25, respectively, and was not mediated through activation of the human orphan nuclear receptor SXR/NR1I2. Importantly, chronic imatinib exposure of Caco2 cells resulted in a approximately 50% decrease in intracellular accumulation of imatinib, probably by enhanced ABCG2- and ABCB1-mediated efflux, as a result of upregulated expression of these drug pumps. Both ABCG2 and ABCB1 are normally expressed in the gastrointestinal tract and it might be anticipated that drug-induced upregulation of these intestinal pumps could reduce the oral bioavailability of imatinib, representing a novel mechanism of acquired pharmacokinetic drug resistance in cancer patients that are chronically treated with imatinib. | ||||||||
| 122 | 46.88 | 16041242 | 2005.10.18 | + | + | 164Ile allele in the beta2-Adrenergic receptor gene is associated with risk of elevated blood pressure in women. The Copenhagen City Heart Study. | Pharmacogenet Genomics | |
| AA Sethi, A Tybjaerg-Hansen, GB Jensen, BG Nordestgaard, | ||||||||
| OBJECTIVE: Since beta2-adrenergic receptors are important regulators of blood pressure, genetic variation in this receptor could explain risk of elevated blood pressure in selected individuals. We tested the hypothesis that Gly16Arg, Gln27Glu, and Thr164Ile in the beta2-adrenergic receptor gene associated with elevated blood pressure. METHODS: We genotyped 9185 individuals from the adult Danish general population. RESULTS: Allele frequencies of 16Arg, 27Glu, and 164Ile were 0.38, 0.44, and 0.01, respectively. Among women never treated with antihypertensive medication those heterozygous for Thr164Ile versus non-carriers had increased diastolic blood pressure (P=0.02). Women heterozygous for Thr164Ile versus non-carriers had an odds ratio for elevated blood pressure of 1.93 (95% CI: 1.30-2.86). Finally, women double heterozygous for Thr164Ile and Gln27Glu or Gly16Arg versus non-carriers at all 3 loci had an odds ratio for elevated blood pressure of 2.49 (1.28-4.85) or 3.19 (1.46-6.97). In men, blood pressure was not influenced by this genetic variation. CONCLUSION: In women Thr164Ile heterozygosity is associated with increased diastolic blood pressure, and represent a risk factor for elevated blood pressure in women in the general population. This was most pronounced in those women also heterozygous for Gln27Glu or Gly16Arg. | ||||||||
| 123 | 46.79 | 11736864 | 2002.03.06 | + | + | An interaction between the cytochrome P450 probe substrates chlorzoxazone (CYP2E1) and midazolam (CYP3A). | Br J Clin Pharmacol | |
| JL Palmer, RJ Scott, A Gibson, M Dickins, S Pleasance, | ||||||||
| AIMS: The use of multiple probe substrates to evaluate the activity of drug metabolizing enzymes requires that there are no inter-substrate interactions. As part of a series of studies to develop a clinically useful collection of probe substrates that could be given alone or in any combination, we observed an interaction between midazolam (MDZ) and another component of the six-drug cocktail. Published data indicated that the interacting component was likely to be chlorzoxazone. This was investigated as part of a second study. The data relating to the interaction from both studies are reported here. METHODS: Both studies were performed in 16 healthy subjects. All treatments were given orally after an overnight fast. In study 1, which was performed to a four-period, open, crossover design, subjects received on separate occasions MDZ 5 mg, diclofenac 25 mg, a four drug cocktail (caffeine 100 mg, mephenytoin 100 mg, debrisoquine 10 mg and chlorzoxazone 250 mg) and a six drug cocktail (caffeine 100 mg, mephenytoin 100 mg, debrisoquine 10 mg, chlorzoxazone 250 mg, diclofenac 25 mg and MDZ 5 mg). In study 2, which was performed to a two-period, open, crossover design, subjects received a five drug cocktail (as the six drug cocktail in the first study, but without chlorzoxazone and with diclofenac dose increased to 50 mg) and a six drug cocktail (as five drug cocktail, with chlorzoxazone 250 mg). In both studies, blood samples were taken for measurement of plasma MDZ and 1-hydroxy MDZ (1-OH MDZ) concentrations. In study 1, blood samples were taken up to 12 h post-dose while in study 2 a single sample was taken 2 h after dosing. In study 1, the potential interaction between MDZ and the other components of the six drug cocktail was assessed by comparing AUClast ratios (1-OH MDZ/MDZ) between the two treatments. Additionally, a single sampling timepoint of 2 h post-dose for determination of concentration, rather than AUC, ratios was established. The 2 h plasma concentration ratios from studies 1 and 2 were combined and a pooled analysis performed to compare ratios within each study (to determine the change in ratio when MDZ was dosed with and without chlorzoxazone) and between studies (to determine the consistency of the ratios when MDZ was given either as part of the two six drug cocktails or when given alone and as part of the five drug cocktail). RESULTS: In study 1, both the AUClast ratio and the 2 h post-dose plasma concentration ratio were reduced when MDZ was given as part of the six drug cocktail in comparison with those for MDZ alone. This was the result of an increase in MDZ, rather than decrease in 1-OH MDZ, concentrations and was considered to result from a reduction in first pass metabolism of MDZ. The geometric mean AUClast values (with 95% CI) for MDZ were 95.6 (79.0, 115.7) and 160.4 (133.6, 192.6) microg l(-1) h when given alone and as part of the six drug cocktail, respectively. The corresponding values for 1-OH MDZ were 789.6 (697.6, 893.6) and 791.4 (701.7, 892.6) microg l(-1) h. The ratio of adjusted geometric mean AUClast ratios for the two treatments was 1.82 (90% CI 1.48, 2.23, P < 0.001). The pooled plasma 1-OH MDZ/MDZ ratio data from both studies showed that the differences in MDZ metabolism observed in study 1 were replicated in study 2. The adjusted geometric mean 1-OH MDZ/MDZ ratios when MDZ was given alone and as part of the six drug cocktail were 7.79 and 4.59, respectively, for study 1 (ratio 1.70, 95% CI 1.36, 2.11, P < 0.001) and 7.64 and 4.60 for study 2 (ratio 1.66, 95% CI 1.34, 2.06, P < 0.001). These data indicate that when given orally chlorzoxazone interacts with MDZ, increasing plasma MDZ concentrations. In contrast, there was no difference between the plasma 1-OH MDZ/MDZ ratios when MDZ was given alone and as part of the five drug cocktail indicating that there were no interactions between MDZ and any of the other components of that cocktail. CONCLUSIONS: Chlorzoxazone appears to significantly influence the pharmacokinetics of oral MDZ, probably through inhibition of first pass metabolism by CYP3A in the GI tract. Data from these studies and literature evidence showing a further interaction between chlorzoxazone and CYP1A2 substrates and questions concerning the specificity of chlorzoxazone as a probe substrate for CYP2E1, indicate that the use of chlorzoxazone in multisubstrate probe cocktails should be avoided. | ||||||||
| 124 | 46.72 | 8563772 | 1996.03.06 | + | + | A multifamily study on the relationship between CYP2C19 genotype and s-mephenytoin oxidation phenotype. | Pharmacogenetics | |
| K Brøsen, SM de Morais, UA Meyer, JA Goldstein, | ||||||||
| It has recently been shown that the most common mutation (named m1) in both Caucasian and Japanese poor metabolizers (PM) of S-mephenytoin is a single base pair mutation (G-->A) in exon 5 of the CYP2C19 gene. In Japanese, a second defective allele of CYP2C19 named m2 consists of a G-->A mutation in exon 4. In the present study, we have investigated the inheritance of the CYP2C19 wild type allele (wt) and the two defective alleles (m1 and m2) in families of 11 Danish PM probands. The study was carried out for two principal reasons. First, we wanted to confirm the autosomal recessive inheritance of the defective alleles, and second, we wanted to examine the specificity and sensitivity of the CYP2C19 genotyping test. Individuals were phenotyped by measuring the ratio of S/R mephenytoin excreted in the urine after administration of mephenytoin, and genotyping was carried out by a PCR-based DNA amplification procedure. The genotypes of nine of the 11 probands were consistent with their phenotypes. Eight were homozygous m1/m1, and one was heterozygous m1/m2. The genotypes of two putative PM probands (wt/m1) were not consistent with their phenotypes. On the basis of extended phenotyping (additional late urine collections (24-36 h) and acidification of urine), one of these could probably be reclassified as an extensive metabolizer (EM) while the other was considered to be a true PM. This suggests the presence of an additional unknown mutant allele in the latter. Seven of the 41 phenotyped relatives in the 11 families were phenotyped as PMs, and with the exception of the father of family 10, their genotypes (m1/m1) were consistent with their phenotypes. Extended phenotyping (acidification of urine) suggested that the father of family 10 in fact is an EM and hence that his genotype (wt/m1) is concordant with his phenotype. Thus, the specificity of genotyping tests for PM was 100%, while the sensitivity was 15/16 or 94%. Our study provides unequivocal evidence for autosomal recessive inheritance of the PM trait. | ||||||||
| 125 | 46.51 | 8195181 | 1994.06.30 | + | + | The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. | J Biol Chem | |
| SM de Morais, GR Wilkinson, J Blaisdell, K Nakamura, UA Meyer, JA Goldstein, | ||||||||
| The metabolism of the anticonvulsant drug mephenytoin exhibits a genetic polymorphism in humans, with the poor metabolizer trait being inherited in an autosomal recessive fashion. There are large interracial differences in the frequency of the poor metabolizer phenotype, with Oriental populations having a 5-fold greater frequency compared to Caucasians. Impaired metabolism of mephenytoin and a number of other currently used drugs results from a defect in a cytochrome P450 enzyme recently identified as CYP2C19. Attempts over the past decade to define the molecular genetic basis of the polymorphism have, however, been unsuccessful. We now report that the principal defect in poor metabolizers is a single base pair (G-->A) mutation in exon 5 of CYP2C19, which creates an aberrant splice site. This change alters the reading frame of the mRNA starting with amino acid 215 and produces a premature stop codon 20 amino acids downstream, which results in a truncated, non-functional protein. We further demonstrate that 7/10 Caucasian and 10/17 Japanese poor metabolizers are homozygous for this defect, indicating that this is the major defect responsible for the poor metabolizer phenotype. Finally, the familial inheritance of the deficient allele was found to be concordant with that of the phenotypic trait. | ||||||||
| 126 | 46.47 | 11505222 | 2001.10.11 | + | + | Association of GSTT1 non-null and NAT1 slow/rapid genotypes with von Hippel-Lindau tumour suppressor gene transversions in sporadic renal cell carcinoma. | Pharmacogenetics | |
| C Gallou, S Longuemaux, C Deloménie, A Méjean, N Martin, S Martinet, G Palais, R Bouvier, D Droz, R Krishnamoorthy, C Junien, C Béroud, JM Dupret, | ||||||||
| The von Hippel-Lindau (VHL) tumour suppressor gene is commonly mutated in renal cell carcinoma of clear cell type (CCRCC). We investigated the possible relationship between VHL mutations in sporadic CCRCC and polymorphism of genes encoding enzymes involved in carcinogen metabolism: two cytochrome P450 monooxygenases (CYP1A1 and CYP2D6), one NAD[P]H:quinone oxidoreductase (NQO1), three glutathione S-transferases (GSTM1, GSTT1 and GSTP1) and two arylamine N-acetyltransferases (NAT1 and NAT2). We analysed DNA from tumour and nontumoural kidney tissue from 195 CCRCC patients. Single VHL mutations were identified in 88 patients and double mutations were present in two patients. Nine of 18 transversions were GC to TA, four were AT to TA, four were GC to CG and one was AT to CG. Ten of 19 transitions were GC to AT and nine were AT to GC. We also identified 53 frameshifts and two GC to AT at CpG. An excess of transversions was observed in a subset of patients with active GSTT1 [GSTT1 (+) genotype] and probably defective NAT1 (NAT1 S/R variant genotype). All 18 transversions were in GSTT1 (+) patients, whereas only 76% of transitions (P = 0.05) and 81% of the other mutations (P = 0.06) occurred in this genotype. We found that 28% of the transversions were in the NAT1 S/R genotype versus 12% of the transitions (P = 0.40) and 4% of the other mutations (P = 0.01). This suggests that pharmacogenetic polymorphisms may be associated with the type of acquired VHL mutation, which may modulate CCRCC development. | ||||||||
| 127 | 46.44 | 16614226 | 2006.04.27 | + | + | A common genetic variant is associated with adult and childhood obesity. | Science | |
| A Herbert, NP Gerry, MB McQueen, IM Heid, A Pfeufer, T Illig, HE Wichmann, T Meitinger, D Hunter, FB Hu, G Colditz, A Hinney, J Hebebrand, K Koberwitz, X Zhu, R Cooper, K Ardlie, H Lyon, JN Hirschhorn, NM Laird, ME Lenburg, C Lange, MF Christman, | ||||||||
| Obesity is a heritable trait and a risk factor for many common diseases such as type 2 diabetes, heart disease, and hypertension. We used a dense whole-genome scan of DNA samples from the Framingham Heart Study participants to identify a common genetic variant near the INSIG2 gene associated with obesity. We have replicated the finding in four separate samples composed of individuals of Western European ancestry, African Americans, and children. The obesity-predisposing genotype is present in 10% of individuals. Our study suggests that common genetic polymorphisms are important determinants of obesity. | ||||||||
| 128 | 46.38 | 10752642 | 2000.06.02 | + | + | Effect of troglitazone on cytochrome P450 enzymes in primary cultures of human and rat hepatocytes. | Xenobiotica | |
| J Sahi, G Hamilton, M Sinz, S Barros, SM Huang, LJ Lesko, EL LeCluyse, | ||||||||
| 1. Troglitazone was the first thiazolidinedione approved for clinical use in the treatment of non-insulin-dependent diabetes mellitus. During clinical investigations of drug-drug interactions with therapeutics (terfenadine and cyclosporine) known to be metabolized by CYP3A4, pharmacokinetic interactions were noted upon troglitazone multiple-dose treatments. The nature of the interactions suggested induction of CYP3A enzymes. 2. Primary cultures of human hepatocytes were used to investigate the induction potential of troglitazone with respect to CYP3A4, CYP2B6 and CYP1A1/2. In human hepatocytes, troglitazone induced both immunoreactive CYP3A4 protein and testosterone 6beta-hydroxylase activity in a dose-dependent fashion (EC50 = 5-10 microM), accompanied by an increase in CYP3A4 mRNA. The capacity of troglitazone to induce CYP3A4 was between that of rifampin (EC50 = 0.8 microM) and dexamethasone (40-50 microM). Troglitazone increased CYP2B6 immunoreactive protein but did not significantly effect CYP1A1/2 activity, immunoreactive protein or mRNA. 3. Troglitazone produced significant increases in CYP3A message, protein and activity in primary rat hepatocytes, a slight increase in CYP2B1/2 activity and no change in CYP1A1/2 message or activity. 4. These results provide evidence that troglitazone can induce CYP3A and CYP2B enzymes while apparently not altering CYP1A. This provides a rationale for the clinically observed interactions of troglitazone with selected CYP3A4 substrates. | ||||||||
| 129 | 46.32 | 11337937 | 2001.09.13 | + | + | MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. | Pharmacogenetics | |
| MM Ameyaw, F Regateiro, T Li, X Liu, M Tariq, A Mobarek, N Thornton, GO Folayan, J Githang'a, A Indalo, D Ofori-Adjei, DA Price-Evans, HL McLeod, | ||||||||
| P-glycoprotein (PGP), the product of the multidrug resistance gene (MDR1), acts as an energy-dependent efflux pump that exports its substrates out of the cell. PGP expression is an important factor regulating absorption of a wide variety of medications. It has also been associated with intrinsic and acquired cross resistance to a number of structurally unrelated anticancer drugs. A single nucleotide polymorphism (SNP) in exon 26 of the MDR1 gene, C3435T, was recently correlated with PGP protein levels and substrate uptake. Individuals homozygous for the T allele have more than four-fold lower PGP expression compared with CC individuals. As overexpression of PGP has been associated with altered drug absorption, therapy-resistant malignancies, and lower concentrations of HIV-1 protease inhibitors, this SNP may provide a useful approach to individualize therapy. To facilitate clinical application throughout the world, 1280 subjects from 10 different ethnic groups were evaluated for this SNP using the polymerase chain reaction-restriction fragment length polymorphism assay and the genotype and allele frequency for each group were ascertained. Marked differences in genotype and allele frequency were apparent between the African populations and the Caucasian/Asian populations (P < 0.0001). The Ghanaian, Kenyan, African American and Sudanese populations studied had frequencies of 83%, 83%, 84% and 73%, respectively, for the C allele. The British Caucasian, Portuguese, South-west Asian, Chinese, Filipino and Saudi populations had lower frequencies of the C allele compared to the African group (48%, 43%, 34%, 53%, 59%, and 55%, respectively). The high frequency of the C allele in the African group implies overexpression of PGP and may have important therapeutic and prognostic implications for use of PGP dependent drugs in individuals of African origin. | ||||||||
| 130 | 46.29 | 15922487 | 2006.02.23 | + | + | Polymorphisms in folate metabolic genes and lung cancer risk in Xuan Wei, China. | Lung Cancer | |
| M Shen, N Rothman, SI Berndt, X He, M Yeager, R Welch, S Chanock, N Caporaso, Q Lan, | ||||||||
| The aim of this study is to investigate the role of genetic polymorphisms in twelve folate metabolism genes on the risk of lung cancer in Xuan Wei, China, where the lung cancer mortality rate is among the highest and is mainly caused by indoor smoky coal emissions. A total of 122 incident primary lung cancer cases and 122 matched controls were enrolled. Three single nucleotide polymorphisms were associated with increased risk of lung cancer including homozygotes of the C allele of CBS Ala360Ala (OR: 4.02; 95% CI: 1.64-9.87), the 222Val allele of MTHFR (OR: 2.32; 95% CI: 1.34-4.03), and the C allele of SLC19A1 Pro232Pro (OR: 1.83; 95% CI: 1.02-3.28). The distribution of CBS and MTHFR haplotypes differed between cases and controls (P=0.002 and P=0.07, respectively). In summary, three genetic variants in folate metabolism genes are associated with an increased risk of lung cancer in Xuan Wei, China. | ||||||||
| 131 | 46.27 | 8880055 | 1997.01.21 | + | + | Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. | Eur J Clin Pharmacol | |
| U Jeppesen, LF Gram, K Vistisen, S Loft, HE Poulsen, K Brøsen, | ||||||||
| OBJECTIVE: The purpose of this pharmacokinetic study was to investigate the dose-dependent inhibition of model substrates for CYP2D6, CYP2C19 and CYP1A2 by four marketed selective serotonin reuptake inhibitors (SSRIs): citalopram, fluoxetine, fluvoxamine and paroxetine. METHODS: The study was carried out as an in vivo single-dose study including 24 young, healthy men. All volunteers had been identified as sparteine- and mephenytoin-extensive metabolisers. The volunteers received in randomised order, at weekly intervals, increasing single oral doses of one of the four SSRIs, followed 3 h later by sparteine (CYP2D6), mephenytoin (CYP2C19) and caffeine (CYP1A2) tests. Fluoxetine was given at 3-week intervals because of the long half-life of fluoxetine and its metabolite norfluoxetine. Citalopram, fluoxetine and paroxetine were given in doses of 10, 20, 40 and 80 mg and fluvoxamine was given in doses of 25, 50, 100 and 200 mg. RESULTS: With increasing doses, there was a statistically significant increase in the sparteine metabolic ratio (MR) (P < 0.01, Page's test for trend) for all four SSRIs. The increase was modest after intake of citalopram and fluvoxamine, while the increase was more pronounced after fluoxetine intake, although no volunteers changed phenotype from extensive metabolisers to poor metabolisers. Three of the six volunteers changed phenotype from extensive metabolisers to poor metabolisers after intake of 40 or 80 mg paroxetine. There was a statistically significant increase in the mephenytoin S/R ratio (P < 0.01, Page's test for trend) with increasing doses of fluoxetine and fluvoxamine, but not after citalopram and paroxetine. However, no volunteers changed phenotype from extensive to poor metabolisers of S-mephenytoin. After intake of fluvoxamine, the urinary excretion of the metabolites related to N3 demethylation of caffeine were below the limit of quantification, whereas there were no significant changes in the urinary caffeine metabolic ratios after intake of the other three SSRIs. CONCLUSION: This investigation confirms that paroxetine and fluoxetine are potent inhibitors of CYP2D6, that fluvoxamine and fluoxetine are moderate inhibitors of CYP2C19 and that fluvoxamine is a potent inhibitor of CYP1A2 in humans in vivo. The clinical prediction of interaction from single-dose experiments may have to take the degree of accumulation during steady-state after multiple doses into account. | ||||||||
| 132 | 46.24 | 17503328 | 2007.06.26 | + | + | IRAK-M is involved in the pathogenesis of early-onset persistent asthma. | Am J Hum Genet | |
| L Balaci, MC Spada, N Olla, G Sole, L Loddo, F Anedda, S Naitza, MA Zuncheddu, A Maschio, D Altea, M Uda, S Pilia, S Sanna, M Masala, L Crisponi, M Fattori, M Devoto, S Doratiotto, S Rassu, S Mereu, E Giua, NG Cadeddu, R Atzeni, U Pelosi, A Corrias, R Perra, PL Torrazza, P Pirina, F Ginesu, S Marcias, MG Schintu, GS Del Giacco, PE Manconi, G Malerba, A Bisognin, E Trabetti, A Boner, L Pescollderungg, PF Pignatti, D Schlessinger, A Cao, G Pilia, | ||||||||
| Asthma is a multifactorial disease influenced by genetic and environmental factors. In the past decade, several loci and >100 genes have been found to be associated with the disease in at least one population. Among these loci, region 12q13-24 has been implicated in asthma etiology in multiple populations, suggesting that it harbors one or more asthma susceptibility genes. We performed linkage and association analyses by transmission/disequilibrium test and case-control analysis in the candidate region 12q13-24, using the Sardinian founder population, in which limited heterogeneity of pathogenetic alleles for monogenic and complex disorders as well as of environmental conditions should facilitate the study of multifactorial traits. We analyzed our cohort, using a cutoff age of 13 years at asthma onset, and detected significant linkage to a portion of 12q13-24. We identified IRAK-M as the gene contributing to the linkage and showed that it is associated with early-onset persistent asthma. We defined protective and predisposing SNP haplotypes and replicated associations in an outbred Italian population. Sequence analysis in patients found mutations, including inactivating lesions, in the IRAK-M coding region. Immunohistochemistry of lung biopsies showed that IRAK-M is highly expressed in epithelial cells. We report that IRAK-M is involved in the pathogenesis of early-onset persistent asthma. IRAK-M, a negative regulator of the Toll-like receptor/IL-1R pathways, is a master regulator of NF- kappa B and inflammation. Our data suggest a mechanistic link between hyperactivation of the innate immune system and chronic airway inflammation and indicate IRAK-M as a potential target for therapeutic intervention against asthma. | ||||||||
| 133 | 46.17 | 9054934 | 1997.04.04 | + | + | A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. | Nat Genet | |
| R Allikmets, N Singh, H Sun, NF Shroyer, A Hutchinson, A Chidambaram, B Gerrard, L Baird, D Stauffer, A Peiffer, A Rattner, P Smallwood, Y Li, KL Anderson, RA Lewis, J Nathans, M Leppert, M Dean, JR Lupski, | ||||||||
| Stargardt disease (STGD, also known as fundus flavimaculatus; FFM) is an autosomal recessive retinal disorder characterized by a juvenile-onset macular dystrophy, alterations of the peripheral retina, and subretinal deposition of lipofuscin-like material. A gene encoding an ATP-binding cassette (ABC) transporter was mapped to the 2-cM (centiMorgan) interval at 1p13-p21 previously shown by linkage analysis to harbour the STGD gene. This gene, ABCR, is expressed exclusively and at high levels in the retina, in rod but not cone photoreceptors, as detected by in situ hybridization. Mutational analysis of ABCR in STGD families revealed a total of 19 different mutations including homozygous mutations in two families with consanguineous parentage. These data indicate that ABCR is the causal gene of STGD/FFM. | ||||||||
| 134 | 46.12 | 16041243 | 2005.10.18 | + | + | Functional characterization of non-synonymous single nucleotide polymorphisms in the gene encoding human multidrug resistance protein 1 (MRP1/ABCC1). | Pharmacogenet Genomics | |
| IJ Létourneau, RG Deeley, SP Cole, | ||||||||
| The 190-kDa ATP-binding cassette (ABC) multidrug resistance protein 1 (MRP1) encoded by the MRP1/ABCC1 gene mediates the active cellular efflux of glucuronide, glutathione and sulfate conjugates. It can also confer resistance to a diverse spectrum of chemotherapeutic agents and transport a variety of toxicants. In the present study, we examined 10 MRP1/ABCC1 missense genetic variants [non-synonymous single nucleotide polymorphisms (SNPs)] to determine whether or not they affect expression or function of the transporter. Variants 218C>T (Thr73Ile), 257C>T (Ser92Phe), 350C>T (Thr117Met), 689G>A (Arg230Gln), 1898G>A (Arg633Gln), 2168G>A (Arg723Gln), 2965G>A (Ala989Thr), 3140G>C (Cys1047Ser), 3173G>A (Arg1058Gln) and 4535C>T (Ser1512Leu) were recreated using site-directed mutagenesis and transfected into human embryonic kidney cells. Immunoblotting experiments showed that all mutant proteins were expressed at levels comparable to wild-type MRP1. Vesicular transport assays revealed that the Ala989Thr mutation caused a significant decrease in estradiol 17beta-glucuronide transport due to a decrease in apparent affinity (Km) for this organic anion. The transport properties of the other mutants were comparable to wild-type MRP1. When the MRP1/ABCC1 non-synonymous SNPs were evaluated by the SIFT algorithm using subsets of homologs and orthologs of MRP1/ABCC1, Arg230Gln, Val353Met, Arg433Ser, Gly671Val and Arg1058 mutations were predicted to be deleterious, whereas the PolyPhen algorithm predicted Ser92Phe and Gly671Val to be potentially damaging. Thus most predictions of these algorithms were not in accordance with our experimental results. In conclusion, our data suggest that none of the MRP1/ABCC1 variants studied are likely by themselves to have major deleterious effects in healthy individuals, and the SIFT and PolyPhen algorithms appear to be poor predictors of the phenotypic consequences of these MRP1 mutations at least in vitro. | ||||||||
| 135 | 46.11 | 15297419 | 2005.03.07 | + | + | Relevance of different UGT1A1 polymorphisms in irinotecan-induced toxicity: a molecular and clinical study of 75 patients. | Clin Cancer Res | |
| E Rouits, M Boisdron-Celle, A Dumont, O Guérin, A Morel, E Gamelin, | ||||||||
| PURPOSE: We wanted to assess polymorphisms in the uridine diphosphoglucuronosyl transferase 1A1 (UGT 1A1) gene: the TATA box polymorphism and UGT 1A1 G71R and Y486D mutations in the coding sequence, the main mutations characterizing Gilbert's syndrome, as predictors of severe toxic event occurrence after irinotecan (CPT-11) administration. Therefore, we set up a rapid, sensitive, and reliable technique in routine practice to detect before CPT-11 treatment, the at-risk patients. EXPERIMENTAL DESIGN: Seventy-five patients with advanced colorectal cancer and treated with CPT-11 and 5-fluorouracil, entered the study. We used the Pyrosequencing technology a real-time sequencing method, to detect the UGT 1A1 TATA box polymorphisms and mutations in the coding regions. Patients were also assessed for both biochemical and clinical evaluation and tolerance to treatment. RESULTS: No G71R and Y486D mutations were found in our population. Frequencies for UGT 1A1 TATA box polymorphisms were 41, 47, and 9% for wild-type 6/6, heterozygous 6/7, and Gilbert's syndrome 7/7, respectively. Tolerance to treatment decreased with increased number of TA repeat with 71% of the patients in 7/7 group who experienced grade 3/4 toxicity. CONCLUSIONS: The method we set up is suitable for the detection of UGT 1A1 polymorphism in routine practice before irinotecan treatment. It could help to detect the patients homozygous or heterozygous for Gilbert's syndrome, at-risk of CPT 11-induced toxicity, and thus could help to individualize the dose to optimize efficacy and limit toxicity. | ||||||||
| 136 | 46.08 | 9811160 | 1999.01.08 | + | + | Multiple human cytochromes contribute to biotransformation of dextromethorphan in-vitro: role of CYP2C9, CYP2C19, CYP2D6, and CYP3A. | J Pharm Pharmacol | |
| LL von Moltke, DJ Greenblatt, JM Grassi, BW Granda, K Venkatakrishnan, J Schmider, JS Harmatz, RI Shader, | ||||||||
| Cytochromes mediating the biotransformation of dextromethorphan to dextrorphan and 3-methoxymorphinan, its principal metabolites in man, have been studied by use of liver microsomes and microsomes containing individual cytochromes expressed by cDNA-transfected human lymphoblastoid cells. In-vitro formation of dextrorphan from dextromethorphan by liver microsomes was mediated principally by a high-affinity enzyme (Km (substrate concentration producing maximum reaction velocity) 3-13 microM). Formation of dextrorphan from 25 microM dextromethorphan was strongly inhibited by quinidine (IC50 (concentration resulting in 50% inhibition) = 0.37 microM); inhibition by sulphaphenazole was approximately 18% and omeprazole and ketoconazole had minimal effect. Dextrorphan was formed from dextromethorphan by microsomes from cDNA-transfected lymphoblastoid cells expressing CYP2C9, -2C19, and -2D6 but not by those expressing CYP1A2, -2E1 or -3A4. Despite the low in-vivo abundance of CYP2D6, this cytochrome was identified as the dominant enzyme mediating dextrorphan formation at substrate concentrations below 10 microM. Formation of 3-methoxy-morphinan from dextromethorphan in liver microsomes proceeded with a mean Km of 259 microM. For formation of 3-methoxymorphinan from 25 microM dextromethorphan the IC50 for ketoconazole was 1.15 microM; sulphaphenazole, omeprazole and quinidine had little effect. 3-Methoxymorphinan was formed by microsomes from cDNA-transfected lymphoblastoid cells expressing CYP2C9, -2C19, -2D6, and -3A4, but not by those expressing CYP1A2 or -2E1. CYP2C19 had the highest affinity (Km = 49 microM) whereas CYP3A4 had the lowest (Km = 1155 microM). Relative abundances of the four cytochromes were determined in liver microsomes by use of the relative activity factor approach. After adjustment for relative abundance, CYP3A4 was identified as the dominant enzyme mediating 3-methoxymorphinan formation from dextromethorphan, although CYP2C9 and -2C19 were estimated to contribute to 3-methoxymorphinan formation, particularly at low substrate concentrations. Although formation of dextrorphan from dextromethorphan appears to be sufficiently specific to be used as an in-vitro or in-vivo index reaction for profiling of CYP2D6 activity, the findings raise questions about the specificity of 3-methoxymorphinan formation as an index of CYP3A activity. | ||||||||
| 137 | 45.98 | 8747406 | 1996.10.24 | + | + | Genetic polymorphism of cytochrome P4502E1 and risk of alcoholic liver disease in Caucasians. | Pharmacogenetics | |
| M Pirmohamed, NR Kitteringham, LJ Quest, RL Allott, VJ Green, IT Gilmore, BK Park, | ||||||||
| Genetic factors may be of importance in determining inter-individual susceptibility to alcoholic liver disease (ALD). Among the candidate genes which have been considered to be important are those which code for enzymes involved in alcohol metabolism. Cytochrome P4502E1 (CYP2E1) metabolizes alcohol to acetaldehyde and the hydroxyethyl radical, and is also inducible by alcohol. A Rsa I restriction fragment length polymorphism (RFLP) in the 5'-flanking region of the CYP2E1 gene has been identified by other investigators, studies showing that the mutant allele (termed c2) shows greater transcriptional activity, higher protein levels and increased activity compared with the wild-type allele (c1). We have used PCR-RFLP analysis to determine whether the frequency of these alleles differed in 95 Caucasian patients with ALD compared with 205 control subjects (comprising 58 alcoholics with no liver disease, 47 patients with non-alcoholic liver disease and 100 healthy volunteers). In controls, the frequency (0.024) of the c2 allele was similar to that previously reported in other Caucasian populations. The c2 allele frequency in patients with ALD (0.1), however, was significantly (p = 0.0003; odds ratio (OR) 4.5, 95% CI 1.9-10.9) higher than in control subjects. The findings indicate that Caucasians carrying the Rsa I c2 allele of the CYP2E1 gene may be at higher risk of developing ALD if they abuse alcohol. | ||||||||
| 138 | 45.96 | 11719732 | 2001.12.20 | + | + | Assessment of cytochrome P450 activity by a five-drug cocktail approach. | Clin Pharmacol Ther | |
| B Zhu, DS Ou-Yang, XP Chen, SL Huang, ZR Tan, N He, HH Zhou, | ||||||||
| OBJECTIVES: Our goal was to establish and validate a modified cocktail approach including probe drugs caffeine, chlorzoxazone, mephenytoin, metoprolol, and midazolam for simultaneous phenotyping of CYP1A2, CYP2E1, CYP2C19, CYP2D6, and CYP3A. METHODS: The study was conducted in 14 healthy, nonsmoking male volunteers with a cocktail of 5 drugs consisting of 100 mg caffeine, 200 mg chlorzoxazone, 100 mg mephenytoin, 100 mg metoprolol, and 7.5 mg midazolam in a randomized manner with a 7 x 7 Latin square design. Plasma was obtained at 1, 4, and 6 hours, and urine was collected from 0 to 8 hours after oral drug administration. RESULTS: The phenotypic indexes determined for caffeine, chlorzoxazone, mephenytoin, metoprolol, and midazolam were not significantly different when the drugs were given in different combinations. There were no metabolic interactions or analytic interference of these probe drugs. CONCLUSIONS: This cocktail approach can simultaneously provide independent in vivo phenotypic measures for the cytochrome P450 (CYP) enzymes CYP1A2, CYP2E1, CYP2C19, CYP2D6, and CYP3A. | ||||||||
| 139 | 45.94 | 15342443 | 2005.02.02 | + | + | Associations between two common variants C677T and A1298C in the methylenetetrahydrofolate reductase gene and measures of folate metabolism and DNA stability (strand breaks, misincorporated uracil, and DNA methylation status) in human lymphocytes in vivo. | Cancer Epidemiol Biomarkers Prev | |
| S Narayanan, J McConnell, J Little, L Sharp, CJ Piyathilake, H Powers, G Basten, SJ Duthie, | ||||||||
| OBJECTIVE: Homozygosity for variants of the methylenetetrahydrofolate reductase (MTHFR) gene is associated with decreased risk for colorectal cancer. We have investigated the relationships between two variants of the MTHFR gene (C677T and A1298C) and blood folate, homocysteine, and genomic stability (strand breakage, misincorporated uracil, and global cytosine methylation in lymphocytes) in a study of 199 subjects. RESULTS: The frequencies of homozygosity for the C677T and A1298C variants of the MTHFR gene were 12.6% and 14.6%, respectively. Plasma homocysteine, folate, vitamin B12, 5-methyltetrahydrofolate, and RBC folate were determined in the C677T genotypes. Plasma folate was significantly lower (P < 0.001) in the homozygous variants (6.7 +/- 0.6 ng/mL) compared with wild-types (8.8 +/- 0.4 ng/mL) and heterozygotes (9.1 +/- 0.5 ng/mL). Homocysteine was significantly higher (P < 0.05) in homozygous variants (13.2 +/- 1.1 micromol/L) compared with homozygous subjects (10.9 +/- 0.4 micromol/L). Homozygous variants had significantly lower (P < 0.05) RBC folate (84.7 +/- 6.3 ng/mL) compared with wild-types (112.2 +/- 5.2 ng/mL) and heterozygous individuals (125.1 +/- 6.6 ng/mL). No significant difference in RBC folate was observed between wild-types and heterozygotes. The A1298C variant did not influence plasma homocysteine, folate, 5-methyltetrahydrofolate, vitamin B12, or RBC folate. Lymphocyte DNA stability biomarkers (strand breaks, misincorporated uracil, and global DNA methylation) were similar for all MTHFR C677T or A1298C variants. CONCLUSION: Data from this study do not support the hypothesis that polymorphisms in the MTHFR gene increase DNA stability by sequestering 5,10-methylenetetrahydrofolate for thymidine synthesis and reducing uracil misincorporation into DNA. | ||||||||
| 140 | 45.90 | 9014202 | 1997.04.10 | + | + | Lung cancer risk in relation to the CYP2C9*1/CYP2C9*2 genetic polymorphism among African-Americans and Caucasians in Los Angeles County, California. | Pharmacogenetics | |
| SJ London, AK Daly, JB Leathart, WC Navidi, JR Idle, | ||||||||
| CYP2C9 is involved in the metabolism of warfarin and a wide array of other therapeutic agents. It also appears to play a role, along with other cytochrome P450 enzymes, in the metabolism of benzo[a]pyrene, a carcinogen in tobacco smoke. A relatively common allelic variant (termed R144C, Cys144 or more recently CYP2C9*2) has been described that results in the substitution of cysteine for arginine at residue 144 and appears to reduce enzyme activity. We therefore examined the possible association between the presence of the CYP2C9*2 variant allele and risk of lung cancer using peripheral blood DNA from 329 incident cases of lung cancer (152 African-American and 177 Caucasian) and 700 (239 African-American and 461 Caucasian) population controls in Los Angeles County, California. Among the population controls the frequency of the CYP2C9*2 variant allele was lower (p = 0.00002) among African-Americans (0.036) than among Caucasians (0.100). The presence of the CYP2C9*2 variant allele was not associated with a decreased risk of lung cancer; slight but nonstatistically significant elevations in risk were observed for both African-Americans [odds ratio (OR) 1.22, 95% confidence interval (CI) 0.48-3.11] and Caucasians (OR = 1.55, 95% CI 0.96-2.48). The ORs were slightly and nonsignificantly elevated for all histologic types without substantive variation. The association also did not vary materially according to smoking history or whether subjects had the homozygous deletion of the GSTM1 gene. We found no support for the hypothesis that the CYP2C9*2 variant allele decreases the risk of lung cancer. The role of P450s, including CYP2C9, in benzo[a]pyrene metabolism is not fully defined, and CYP2C9 catalyses detoxication as well as activation steps. Thus it is not inconceivable that diminished CYP2C9 activity could increase metabolic activation of benzo[a]pyrene to carcinogenic intermediates. Nonetheless, the small increased risk associated the CYP2C9*2 variant allele in our data is consistent with chance and should not be overinterpreted. | ||||||||
| 141 | 45.86 | 14743364 | 2004.08.31 | + | + | DNA sequence analysis of monoamine oxidase B gene coding and promoter regions in Parkinson's disease cases and unrelated controls. | Mov Disord | |
| P Costa-Mallen, Z Afsharinejad, SN Kelada, LG Costa, GM Franklin, PD Swanson, WT Longstreth, HM Viernes, FM Farin, T Smith-Weller, H Checkoway, | ||||||||
| The allele G of the intron 13 G/A polymorphism of the monoamine oxidase B gene (MAO-B) has been associated with Parkinson's disease (PD) in several studies. Apart from a potential direct effect on splicing processes, the association of this intronic polymorphism with PD is due possibly to linkage disequilibrium with other mutations in the coding or promoter regions of the gene. We addressed this latter hypothesis by determining the DNA sequence of the entire MAO-B coding region comprising 15 exons and partial intronic sequences flanking each exon, in 33 cases with idiopathic PD and 38 unrelated controls. The promoter region of MAO-B gene up to base -1,369 from ATG (start point of mRNA translation) was also sequenced to identify variants with potential functional effects on gene transcription. In the promoter region, a new polymorphism consisting of a C to T single base change was detected in position -1,114 from ATG, with an allelic frequency of 3.5%, but it was not associated with PD risk. No commonly occurring (>10%) polymorphisms were found in the exons or the intronic sequences flanking the exons, although several rare variants were detected in the coding and promoter regions. | ||||||||
| 142 | 45.81 | 11840287 | 2002.03.07 | + | + | Effect of methotrexate polyglutamates on thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with mercaptopurine. | Leukemia | |
| T Dervieux, M Hancock, W Evans, CH Pui, MV Relling, | ||||||||
| Methotrexate is widely administered with mercaptopurine, a prodrug requiring activation into thioguanine nucleotides (TGN) to exert antileukemic effects. In vitro, methotrexate enhances TGN formation, but in vivo, such enhancement has yet to be demonstrated. We investigated whether TGN concentrations were related to methotrexate concentrations in children with acute lymphoblastic leukemia who received a weekly intravenous methotrexate (40 mg/m(2)) dose combined with daily mercaptopurine (75 mg/m(2)). A total of 141 erythrocyte TGN concentrations were measured with erythrocyte methotrexate polyglutamates (MTX-PG) concentrations in 87 patients. Average TGN concentrations ranged from 137 to 958 pmol/8 x 10(8) cells (median 389), average total MTX-PG concentrations (MTX- PG(1-7)) from 0.60 to 97.7 pmol/10(9)cells (median 29), and average long chain polyglutamate concentrations (MTX-PG(5-7)) from 0 to 8.35 pmol/10(9) cells (median 2.43). Higher TGN concentrations correlated with higher MTX-PG(5-7) concentrations (P = 0.002). These data support the practice of administering methotrexate with mercaptopurine during continuation therapy of acute lymphoblastic leukemia. | ||||||||
| 143 | 45.74 | 15108191 | 2004.11.02 | + | + | Linkage and association analysis at the serotonin transporter (SLC6A4) locus in a rigid-compulsive subset of autism. | Am J Med Genet B Neuropsychiatr Genet | |
| JL McCauley, LM Olson, M Dowd, T Amin, A Steele, RD Blakely, SE Folstein, JL Haines, JS Sutcliffe, | ||||||||
| Autism is a complex genetic neurodevelopmental disorder in which affected individuals display deficits in language, social relationships, and patterns of compulsive and stereotyped behaviors and rigidity. Linkage analysis in our dataset of 57 New England and 80 AGRE multiplex autism families reveals a multipoint heterogeneity LOD (HLOD) score of 2.74 at D17S1871 in 17q11.2. Analysis of phenotypic subsets shows an increased HLOD of 3.62 in families with compulsive behaviors and rigidity. The serotonin transporter locus (SLC6A4) maps nearby and is considered a functional candidate gene in autism and obsessive-compulsive disorder. We genotyped an insertion/deletion polymorphism in the promoter (5-HTTLPR), and seven single nucleotide polymorphisms (SNPs) across the 38-kb transcriptional unit. Transmission disequilibrium (TD) analysis reveals nominal association at a SNP in intron 5 (P = 0.02) as well as 5-HTTLPR (P = 0.01), corresponding to over-transmission of the short allele. TD analysis in the rigid-compulsive subset shows no evidence for association. Intermarker linkage disequilibrium was determined. All SNPs define a single haplotype block, while 5-HTTLPR lies 5' to this block. Three SNPs are sufficient to detect all common alleles (> or =5%) in this > 26-kb block. Analysis of haplotypes for these markers demonstrates no evidence for association to autism. These data indicate that a common allele within the coding region of SLC6A4 is not responsible for the observed linkage. However, the presence of heterogeneous disease variants within the block or the existence of a common disease-associated allele either upstream or downstream of this block is possible. In fact, such variants may well account for linkage to 17q11.2 in our families. | ||||||||
| 144 | 45.73 | 10886115 | 2000.09.14 | + | + | Frequencies of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity of dextromethorphan O-demethylation in different CYP2D6 genotypes. | Br J Clin Pharmacol | |
| T Kubota, Y Yamaura, N Ohkawa, H Hara, K Chiba, | ||||||||
| AIMS: To determine the frequencies of 11 CYP2D6 mutant alleles (CYP2D6*2, *3, *4, *5, *8, *10, *11, *12, *14, *17 and *18), and their relation to the metabolic capacity of CYP2D6 in Japanese subjects. METHODS: One hundred and sixty-two unrelated healthy Japanese subjects were genotyped with the polymerase chain reaction amplification method and 35 subjects were phenotyped with dextromethorphan. RESULTS: The frequencies of CYP2D6*2,*5, *10 and *14 were 12.9, 6.2, 38.6 and 2.2% in our Japanese subjects, respectively. CYP2D6*3, *4, *8, *11, *12, *17 and *18 were not detected. The mean log metabolic ratio of dextromethorphan in subjects with genotypes predicting intermediate metabolizers was significantly greater than that of heterozygotes for functional and defective alleles. CONCLUSIONS: CYP2D6*5 and CYP2D6*14 are the major defective alleles found in Japanese subjects. In addition, CYP2D6*10 may play a more important role than previously thought for the treatment of Japanese patients with drugs metabolized by CYP2D6. | ||||||||
| 145 | 45.66 | 10578237 | 2000.01.03 | + | + | Identification of a novel polymorphism of the human dopamine transporter (DAT1) gene and the significant association with alcoholism. | Mol Psychiatry | |
| S Ueno, M Nakamura, M Mikami, K Kondoh, H Ishiguro, T Arinami, T Komiyama, H Mitsushio, A Sano, H Tanabe, | ||||||||
| Human dopamine transporter gene (DAT1) has a variable number of tandem repeats (VNTR) in its 3'-untranslated region (UTR). The association between the VNTR polymorphism and neuropsychiatric disorders has been studied, but their relationship is still unclear. Here we identified a novel polymorphism in the 3'-UTR of the DAT1 gene, G2319A, and a significant association between the polymorphism and alcoholism was observed in both genotypic and allelic frequencies (P = 0.040 and 0.019, extended Fisher's exact test, respectively). There was a significant gene dose effect on the risk for alcoholism associated with the 2319-A allele (chi2 = 6.16, df = 2, P = 0.046, linearity tendency test: Cochranq-Armitage analysis). Moreover, in the haplotype analysis with G2319A- and VNTR-polymorphisms, a positive gene dose efffect on the risk with the A10 allele (P = 0.044, linearity tendency test) and a negative gene dose effect with the G10 allele (P = 0.010, linearity tendency test) for alcoholism were significantly detected. Odds ratio for alcoholism with the A10 and G10 alleles were 1.76 (1.12-2.76) and 0.53 (0.32-0.79), respectively. These results indicate that the DAT1 gene may confer vulnerability to alcoholism. | ||||||||
| 146 | 45.64 | 15289788 | 2004.08.24 | + | + | Functional impact of CYP2C95, CYP2C96, CYP2C98, and CYP2C911 in vivo among black Africans. | Clin Pharmacol Ther | |
| AC Allabi, JL Gala, Y Horsmans, MO Babaoglu, A Bozkurt, M Heusterspreute, U Yasar, | ||||||||
| Background and aim Previous data indicate that the urinary losartan/E-3174 ratio is a marker for cytochrome P450 (CYP) 2C9 activity in vivo. The functional impact of CYP2C9*5, *6, *8, and *11 polymorphisms in vivo has not been investigated previously in humans. METHODS: A single oral dose of losartan (25 mg) was given to 19 Beninese subjects with CYP2C9*1/*1 (n = 9), *1/*5 (n = 1), *1/*6 (n = 1), *1/*8 (n = 2), *1/*11 (n = 3), *5/*6 (n = 1), *5/*8 (n = 1), and *8/*11 (n = 1) genotypes. Concentrations of losartan and its active metabolite E-3174 were determined in urine from 0 to 8 hours by HPLC. The losartan/E-3174 metabolic ratio was used as a measure of losartan oxidation in vivo. RESULTS: The urinary losartan/E-3174 ratio in the various genotypes was as follows: 1.85 +/- 2.4 (mean +/- SD) for CYP2C9*1/*1, 14.6 for CYP2C9*1/*5, 4.2 for CYP2C9*1/*6, 188 for CYP2C9*5/*6, 11.6 for CYP2C9*5/*8, 0.44 +/- 0.13 (mean +/- SD) for CYP2C9*1/*8, 2.2 for CYP2C9*8/*11, and 5.72 +/- 4.5 (mean +/- SD) for CYP2C9*1/*11. Compared with the CYP2C9*1/*1 genotypes, the losartan/E-3174 ratio was significantly different in the CYP2C9*5 allele carriers (CYP2C9*1/*5, CYP2C9*5/*8, and CYP2C9*5/*6 genotypes) (P =.01, Mann-Whitney) but was not different in CYP2C9*1/*8 (P =.16) and CYP2C9*1/*11 (P =.11) carriers. The urinary losartan/E-3174 ratio of the single CYP2C9*1/*6 subject was higher than the 95% confidence interval of the mean of the CYP2C9*1/*1 group (0.0-3.7), whereas the metabolic ratio of the CYP2C9*8/*11 carrier was inside the 95% confidence interval of the means of the CYP2C9*1/*1 and CYP2C9*1/*11 groups (0.0-18). CONCLUSIONS: The CYP2C9*5 and *6 alleles are associated with decreased enzyme activity in vivo compared with the wild-type variant, whereas the CYP2C9*8 and *11 variants did not appear to have large in vivo effects. | ||||||||
| 147 | 45.59 | 11179012 | 2001.04.05 | + | + | Compound heterozygosity for a recurrent 16.5-kb Alu-mediated deletion mutation and single-base-pair substitutions in the ABCC6 gene results in pseudoxanthoma elasticum. | Am J Hum Genet | |
| F Ringpfeil, A Nakano, J Uitto, L Pulkkinen, | ||||||||
| Pseudoxanthoma elasticum (PXE) is a systemic heritable disorder affecting the elastic structures in the skin, eyes, and cardiovascular system, with considerable morbidity and mortality. Recently, mutations in the ABCC6 gene (also referred to as "MRP6" or "eMOAT") encoding multidrug-resistance protein 6 (MRP6), a putative transmembrane ABC transporter protein of unknown function, have been disclosed. Most of the genetic lesions delineated thus far consist of single-base-pair substitutions resulting in nonsense, missense, or splice-site mutations. In this study, we examined four multiplex families with PXE inherited in an autosomal recessive pattern. In each family, the proband was a compound heterozygote for a single-base-pair-substitution mutation and a novel, approximately 16.5-kb deletion mutation spanning the site of the single-base-pair substitution in trans. The deletion mutation was shown to extend from intron 22 to intron 29, resulting in out-of-frame deletion of 1,213 nucleotides from the corresponding mRNA and causing elimination of 505 amino acids from the MRP6 polypeptide. The deletion breakpoints were precisely the same in all four families, which were of different ethnic backgrounds, and haplotype analysis by 13 microsatellite markers suggested that the deletion had occurred independently. Deletion breakpoints within introns 22 and 29 were embedded within AluSx repeat sequences, specifically in a 16-bp segment of DNA, suggesting Alu-mediated homologous recombination as a mechanism. | ||||||||
| 148 | 45.52 | 16763017 | 2006.12.04 | + | + | Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11). | Drug Metab Dispos | |
| T Lang, M Haberl, D Jung, A Drescher, R Schlagenhaufer, A Keil, E Mornhinweg, B Stieger, GA Kullak-Ublick, R Kerb, | ||||||||
| Biliary excretion of bile salts and other bile constituents from hepatocytes is mediated by the apical (canalicular) transporters P-glycoprotein 3 (MDR3, ABCB4) and the bile salt export pump (ABCB11). Mutations in ABCB4 and ABCB11 contribute to cholestatic diseases [e.g., progressive familial intrahepatic cholestasis 2 (PFIC2), PFIC3, and intrahepatic cholestasis of pregnancy], and our objective was to establish genetic variability and haplotype structures of ABCB4 and ABCB11 in healthy populations of different ethnic backgrounds. All coding exons, 5 of 6 noncoding exons, 50 to 300 base pairs of the flanking intronic regions, and 2.5 to 2.8 kilobase pairs of the promoter regions of ABCB4 and ABCB11 were sequenced in 159 and 196 DNA samples of Caucasian, African-American, Japanese, and Korean origin. In total, 76 and 86 polymorphisms were identified in ABCB4 and ABCB11, respectively; among them, 14 and 28 exonic polymorphisms, and 8 and 10 protein-altering variants, of which 4 were predicted to have functional consequences. Both genes showed substantial ethnic differences with respect to allele number, frequency of common and population-specific sites, and patterns of linkage disequilibrium. Population genetic analysis suggested some selective pressure against changes in the protein, supporting the important endogenous role of these transporters. Haplotype variability was greater in ABCB11 than in ABCB4. An ABCB11 promoter haplotype was associated with significant decrease of activity compared with wild type. Our results contribute to a better understanding of the molecular basis and of ethnic differences in drug response, and provide a valuable tool for future research on the heredity of cholestatic liver injury. | ||||||||
| 149 | 45.47 | 15761120 | 2005.04.28 | + | + | Complement factor H variant increases the risk of age-related macular degeneration. | Science | |
| JL Haines, MA Hauser, S Schmidt, WK Scott, LM Olson, P Gallins, KL Spencer, SY Kwan, M Noureddine, JR Gilbert, N Schnetz-Boutaud, A Agarwal, EA Postel, MA Pericak-Vance, | ||||||||
| Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness in the elderly whose etiology remains largely unknown. Previous studies identified chromosome 1q32 as harboring a susceptibility locus for AMD. We used single-nucleotide polymorphisms to interrogate this region and identified a strongly associated haplotype in two independent data sets. DNA resequencing of the complement factor H gene within this haplotype revealed a common coding variant, Y402H, that significantly increases the risk for AMD with odds ratios between 2.45 and 5.57. This common variant likely explains approximately 43% of AMD in older adults. | ||||||||
| 150 | 45.47 | 15138999 | 2004.07.27 | + | + | Allele-specific loss of heterozygosity at the DAL-1/4.1B (EPB41L3) tumor-suppressor gene locus in the absence of mutation. | Genes Chromosomes Cancer | |
| K Kittiniyom, M Mastronardi, M Roemer, WA Wells, ER Greenberg, L Titus-Ernstoff, IF Newsham, | ||||||||
| DAL-1/4.1B (EPB41L3)is a member of the protein 4.1 superfamily, which encompasses structural proteins that play important roles in membrane processes via interactions with actin, spectrin, and the cytoplasmic domains of integral membrane proteins. DAL-1/4.1B localizes within chromosomal region 18p11.3, which is affected by loss of heterozygosity (LOH) in various adult tumors. Reintroduction of this protein into DAL-1/4.1B-null lung and breast tumor cell lines significantly reduced the number of cells, providing functional evidence that this protein possesses a growth suppressor function not confined to a single cell type. For characterization of the mutational mechanisms responsible for loss of DAL-1/4.1B function in tumors, the exon-intron structure of DAL-1/4.1B was examined for mutations in 15 normal/tumor pairs of non-small cell lung carcinoma by single-strand conformation polymorphism analysis. These studies revealed that small intragenic mutations are uncommon in DAL-1/4.1B. Furthermore, LOH analysis on 129 informative early-stage breast tumors utilizing a new intragenic C/T single-nucleotide polymorphism in exon 14 revealed that LOH resulted in preferential retention of the C-containing allele, suggesting that allele-specific loss is occurring. These studies indicate that mechanisms such as imprinting or monoallelic expression in combination with loss of heterozygosity may be responsible for loss of the DAL-1/4.1B protein in early breast disease. | ||||||||
| 151 | 45.42 | 17558302 | 2007.08.20 | + | + | CYP2C8 haplotype structures and their influence on pharmacokinetics of paclitaxel in a Japanese population. | Pharmacogenet Genomics | |
| Y Saito, N Katori, A Soyama, Y Nakajima, T Yoshitani, SR Kim, H Fukushima-Uesaka, K Kurose, N Kaniwa, S Ozawa, N Kamatani, K Komamura, S Kamakura, M Kitakaze, H Tomoike, K Sugai, N Minami, H Kimura, Y Goto, H Minami, T Yoshida, H Kunitoh, Y Ohe, N Yamamoto, T Tamura, N Saijo, J Sawada, | ||||||||
| OBJECTIVE: CYP2C8 is known to metabolize various drugs including an anticancer drug paclitaxel. Although large interindividual differences in CYP2C8 enzymatic activity and several nonsynonymous variations were reported, neither haplotype structures nor their associations with pharmacokinetic parameters of paclitaxel were reported. METHODS: Haplotype structures of the CYP2C8 gene were inferred by an expectation-maximization based program using 40 genetic variations detected in 437 Japanese patients, which included cancer patients. Associations of the haplotypes and paclitaxel pharmacokinetic parameters were analyzed for 199 paclitaxel-administered cancer patients. RESULTS: Relatively strong linkage disequilibriums were observed throughout the CYP2C8 gene. We estimated 40 haplotypes without an amino-acid change and nine haplotypes with amino acid changes. The 40 haplotypes were classified into six groups based on network analysis. The patients with heterozygous *IG group haplotypes harboring several intronic variations showed a 2.5-fold higher median area under concentration-time curve of C3'-p-hydroxy-paclitaxel and a 1.6-fold higher median value of C3'-p-hydroxy-paclitaxel/paclitaxel area under concentration-time curve ratio than patients bearing no *IG group haplotypes (P<0.001 for both comparisons by Mann-Whitney U-test). No statistically significant differences, however, were observed between patients with and without the *IG group (haplotypes) in clearance and area under concentration-time curve of paclitaxel, area under concentration-time curve of 6alpha-hydroxy-paclitaxel and 6alpha-, C3'-p-dihydroxy-paclitaxel, and area under concentration-time curve ratio of 6alpha-hydroxy-paclitaxel/paclitaxel. CONCLUSION: CYP2C8*IG group haplotypes were associated with increased area under concentration-time curve of C3'-p-hydroxy-paclitaxel and area under concentration-time curve ratio of C3'-p-hydroxy-paclitaxel/paclitaxel. Thus, *IG group haplotypes might be associated with reduced CYP2C8 activity, possibly through its reduced protein levels. | ||||||||
| 152 | 45.37 | 12754175 | 2004.04.08 | + | + | CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults. | J Appl Physiol | |
| RC Givens, YS Lin, AL Dowling, KE Thummel, JK Lamba, EG Schuetz, PW Stewart, PB Watkins, | ||||||||
| A single-nucleotide polymorphism (A6986G) in the cytochrome p-450 3A5 (CYP3A5) gene distinguishes an expressor (*1) and a reduced-expressor (*3) allele and largely predicts CYP3A5 content in liver and intestine. CYP3A5 is the prevailing CYP3A isoform in kidney. We report that, among renal microsomes from 21 organ donors, those from *1/*3 individuals had at least eightfold higher mean kidney microsomal CYP3A5 content and 18-fold higher mean CYP3A catalytic activity than did those from *3/*3 individuals (P = 0.0001 and P = 0.0137, respectively). We also report significant associations between the A6986G polymorphism and systolic blood pressure (P = 0.0007), mean arterial pressure (P = 0.0075), and creatinine clearance (P = 0.0035) among 25 healthy African-American adults. These associations remained significant when sex, age, and body mass index were taken into account. The mean systolic blood pressure of homozygous CYP3A5 expressors (*1/*1) exceeded that of homozygous nonexpressors (*3/*3) by 19.3 mmHg. We speculate whether a high CYP3A5 expressor allele frequency among African-Americans may contribute to a high prevalence of sodium-sensitive hypertension in this population. | ||||||||
| 153 | 45.34 | 9205829 | 1997.09.19 | + | + | Association between CYP2C19 genotype and proguanil oxidative polymorphism. | Br J Clin Pharmacol | |
| JK Coller, AA Somogyi, F Bochner, | ||||||||
| AIMS: To examine the relationship between proguanil metabolism and the number of mutations in CYP2C19 by comparing the CYP2C19 genotype and proguanil phenotype of 10 subjects. METHODS: Partial clearance and urinary metabolic ratio data were obtained from a previous study of 10 subjects [5]. Analysis of CYP2C19 genotypes was performed using PCR amplification followed by restriction endonuclease digestion of genomic DNA from a blood sample. RESULTS: The intrinsic partial clearance of PG to CG ranged from 0.41-10.11 h-1, and was related to the number of functional CYP2C19 alleles present. Genotypic PMs had metabolic ratios > 13, while genotypic heterozygote EMs had metabolic ratios < 9. CONCLUSIONS: Proguanil may be a suitable phenotyping probe for the CYP2C19 genetic polymorphism, however the exact antimode of the urinary metabolic ratio chosen to separate poor and extensive metabolisers needs further investigation. | ||||||||
| 154 | 45.28 | 9399688 | 1998.01.15 | + | + | Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder. | Mol Psychiatry | |
| H Kunugi, M Hattori, T Kato, M Tatsumi, T Sakai, T Sasaki, T Hirose, S Nanko, | ||||||||
| There is some evidence suggesting that a polymorphism of variable number of tandem repeats (VNTR) in the second intron of the serotonin transporter (5-HTT) gene and another variation which lies 1.2 kb upstream of the promoter of the gene (5-HTTLPR) are associated with affective disorders. However, conflicting results have also been reported. We examined an allelic association of these two polymorphisms in a Japanese sample of 191 patients with affective disorders (142 bipolar and 49 unipolar) and 212 controls. Substantial differences in the number and frequency of alleles between Caucasians and Japanese were observed for both polymorphisms. A significant association between the VNTR polymorphism and bipolar disorder (genotypic association: odds ratio 2.2, 95% CI 1.2-4.0; allelic association: odds ratio 1.7, 95% CI 1.0-3.0) was found, but not between the 5-HTTLPR polymorphism and bipolar disorder. No significant association with unipolar depression was detected using either genetic marker, although this may be attributable to the relatively small number of subjects with unipolar depression. Our results suggest that the VNTR itself or another unknown functional polymorphism which would be in linkage disequilibrium to the VNTR has an effect on susceptibility to bipolar disorder. | ||||||||
| 155 | 45.25 | 11920858 | 2002.06.17 | + | + | Allelic association analysis of the dopamine D2, D3, 5-HT2A, and GABA(A)gamma2 receptors and serotonin transporter genes with heroin abuse in Chinese subjects. | Am J Med Genet | |
| T Li, X Liu, J Zhao, X Hu, DM Ball, el-W Loh, PC Sham, DA Collier, | ||||||||
| Five candidate genes, the receptors DRD2, DRD3, HTR2A and GABA(A)gamma2, and the serotonin transporter (5-HTT) were analyzed for association with heroin abuse. We examined three polymorphisms (promoter - 141DeltaC, Ser311Cys, and TaqI) in the DRD2 gene, one polymorphism (Ser9Gly) in the DRD3 gene, two polymorphisms (promoter - 1438G/A and T102C) in the HTR2A gene, two polymorphisms (VNTR and Del/Ins) in 5-HTT gene, and one polymorphism (G3145A) in GABA(A)gamma2 gene in 121 Chinese heroin addicts and 194 controls. None of the polymorphisms differed significantly for allele, genotype, or haplotype frequencies, except for the DRD2 promoter polymorphism - 141DeltaC (genotype-wise and allele-wise, P = 0.05, uncorrected). An additional 344 subjects with heroin abuse and 104 controls were investigated for the - 141DeltaC polymorphism. In the second sample, there were no significant difference of genotype or allele frequencies between subjects with heroin abuse and normal controls. When we divided the sample by route of administration into nasal inhalers and IM or IV injectors, however, it produced a significant difference between inhalers of heroin and controls (genotype-wise, P = 0.006, allele-wise, P = 0.016) but not for injectors of heroin (genotype-wise, P = 0.81, allele-wise, P = 0.69). We also found that LD between all polymorphisms we examined in the gene was weak, possibly explaining why we see association of this polymorphism with heroin abuse but not with other markers in the gene. Overall our results indicates that the HTR2A, 5-HTT, DRD3 and GABA(A)gamma2 genes are not likely to be a major genetic risk factor for heroin abuse in this population, with the exception of possible association between nasal inhalation and DRD2 promoter - 141DeltaC polymorphism. | ||||||||
| 156 | 45.25 | 12116182 | 2002.10.01 | + | + | Schizophrenia and functional polymorphisms in the MAOA and COMT genes: no evidence for association or epistasis. | Am J Med Genet | |
| N Norton, G Kirov, S Zammit, G Jones, S Jones, R Owen, M Krawczak, NM Williams, MC O'Donovan, MJ Owen, | ||||||||
| Several lines of evidence suggest that psychosis is associated with altered dopaminergic neurotransmission. Dopamine is catabolized by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). We hypothesized that the genes encoding MAOA and COMT might contain genetic variation conferring increased risk to schizophrenia. In order to test this hypothesis, we genotyped the 941T > G and the promoter VNTR polymorphisms in the MAOA gene and the V158M COMT polymorphism in 346 DSMIV schizophrenics and 334 controls. We also genotyped the-287A > G COMT promoter polymorphism in 177 schizophrenics and 173 controls. No significant differences were found in allele or genotype frequencies between affecteds and controls for any of the polymorphisms. As both genes are involved in degrading catecholamines, we also sought evidence for additive and epistatic effects but none was observed. Our data, therefore, do not support the hypothesis that genetic variation in MAOA and COMT is involved individually or in combination in the etiology of schizophrenia. | ||||||||
| 157 | 45.25 | 7909282 | 1994.05.26 | + | + | Genetic basis for differences in debrisoquin polymorphism between a Spanish and other white populations. | Clin Pharmacol Ther | |
| JA Agúndez, C Martínez, MC Ledesma, MG Ladona, JM Ladero, J Benítez, | ||||||||
| The debrisoquin hydroxylation polymorphism is an autosomic recessive trait of the cytochrome P450IID6, an enzyme involved in drug metabolism, that affects 5% to 10% of white subjects. The genetic basis of this polymorphism was studied in 258 unrelated Spanish white subjects. The results revealed that about 5% of the subjects were homozygous for mutant alleles and that about 1% of the subjects carried alleles that suggested CYP2D6 gene duplication. The extensive metabolizers who were homozygous for the wild-type allele had higher metabolic ratio than the heterozygous extensive metabolizers, indicating a gene-dose effect for the wild type allele. The CYP2D6 allele frequencies indicate a reduced frequency for the CYP2D6(B) allele and a higher frequency for the wild-type allele compared with other white populations. This is also reflected in an increased frequency of the subjects who were homozygous for the wild-type allele among extensive metabolizers. We conclude that the same CYP2D6 mutations are present in Spaniards and other white subjects. Nevertheless, the frequencies of such mutations are different in our population. This implies that a high number of Spanish subjects may behave differently than other white subjects in the effect of drugs metabolized by the CYP2D6 enzyme. | ||||||||
| 158 | 45.24 | 15571264 | 2005.02.03 | + | + | The clinical impact of thiopurine methyltransferase polymorphisms on thiopurine treatment. | Nucleosides Nucleotides Nucleic Acids | |
| SA Coulthard, EC Matheson, AG Hall, LA Hogarth, | ||||||||
| Acute lymphoblastic leukaemia (ALL) is the most common malignancy of childhood. Although current treatment results in long term survival in over 70% of cases there is evidence that as many as 50% could have been cured using a less complex regimen with a lower incidence of long term side effects. In previous studies it has been found that thiopurines given as part of continuing therapy are key agents in preventing relapse. However, optimal administration during continuing therapy is often not achieved. Variation in the level of thiopurine methyltransferase (TPMT) activity appears to be a major molecular determinant of the extent of thiopurine metabolism. TPMT activity shows a trimodal distribution pattern. A lack of activity is found in approximately one in 300 Caucasians; approximately 11% have intermediate activity and the remaining 89% high activity. Congenital loss of activity is associated with grossly elevated levels of active drug and profound myelosuppression on exposure to thiopurines. This loss of activity has been attributed to single nucleotide polymorphisms (SNPs) within the TPMT gene. The frequency of SNPs is related to ethnicity, with the most common in Caucasians being TPMT*3A which is characterized by a G to A transition at position 460 with a substitution of alanine for tyrosine at amino acid 154 (A154Y) and a transition of A to G at nucleotide 719 resulting in a change of tyrosine to cysteine at position 240 (Y240C). Polymorphisms have also been identified within the 5' flanking promoter region of the TPMT gene due to a variable number of tandem repeats (VNTR*3-*8). An overview of the polymorphisms identified to date, their implication on the metabolism of the thiopurine drugs and therapeutic importance will be discussed. | ||||||||
| 159 | 45.18 | 10814726 | 2000.08.29 | + | + | Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). | Hum Mol Genet | |
| A Muchir, G Bonne, AJ van der Kooi, M van Meegen, F Baas, PA Bolhuis, M de Visser, K Schwartz, | ||||||||
| LGMD1B is an autosomal dominantly inherited, slowly progressive limb girdle muscular dystrophy, with age-related atrioventricular cardiac conduction disturbances and the absence of early contractures. The disease has been linked to chromosome 1q11-q21. Within this locus another muscular dystrophy, the autosomal dominant form of Emery-Dreifuss muscular dystrophy (AD-EDMD) has recently been mapped and the corresponding gene identified. AD-ADMD is characterized by early contractures of elbows and Achilles tendons and a humero-peroneal distribution of weakness combined with a cardiomyopathy with conduction defects. The disease gene of AD-EDMD is LMNA which encodes lamins A/C, two proteins of the nuclear envelope. In order to identify whether or not LGMD1B and AD-EDMD are allelic disorders, we carried out a search for mutations in the LMNA gene in patients with LGMD1B. For this, PCR/SSCP/sequencing screening was carried out for the 12 exons of LMNA on DNA samples of individuals from three LGMD1B families that were linked to chromo-some 1q11-q21. Mutations were identified in all three LGMD1B families: a missense mutation, a deletion of a codon and a splice donor site mutation, respectively. The three mutations were identified in all affected members of the corresponding families and were absent in 100 unrelated control subjects. The present identification of mutations in the LMNA gene in LGMD1B demonstrates that LGMD1B and AD-EDMD are allelic disorders. Further analysis of phenotype-genotype relationship will help to clarify the variability of the phenotype observed in these two muscular dystrophies. | ||||||||
| 160 | 45.11 | 9361038 | 1998.03.18 | + | + | Low proportion of BRCA1 and BRCA2 mutations in Finnish breast cancer families: evidence for additional susceptibility genes. | Hum Mol Genet | |
| P Vehmanen, LS Friedman, H Eerola, M McClure, B Ward, L Sarantaus, T Kainu, K Syrjäkoski, S Pyrhönen, OP Kallioniemi, T Muhonen, M Luce, TS Frank, H Nevanlinna, | ||||||||
| One hundred breast and breast-ovarian cancer families identified at the Helsinki University Central Hospital in southern Finland and previously screened for mutations in the BRCA2 gene were now analyzed for mutations in the BRCA1 gene. The coding region and splice boundaries of BRCA1 were analyzed by protein truncation test (PTT) and heteroduplex analysis (HA)/SSCP in all 100 families, and 70 were also screened by direct sequencing. Contrary to expectations based on Finnish population history and strong founder effects in several monogenic diseases in Finland, a wide spectrum of BRCA1 and BRCA2 mutations was found. In the BRCA1 gene, 10 different protein truncating mutations were found each in one family. Six of these are novel Finnish mutations and four have been previously found in other European populations. Six different BRCA2 mutations were found in 11 families. Altogether only 21% of the breast cancer families were accounted for by mutations in these two genes. Linkage to both chromosome 17q21 (BRCA1) and 13q12 (BRCA2) was also excluded in a subset of seven mutation-negative families with four or more cases of breast or ovarian cancer. These data indicate that additional breast and breast-ovarian cancer susceptibility genes are likely to be important in Finland. | ||||||||
| 161 | 45.10 | 10220144 | 1999.06.10 | + | + | Novel KCNQ1 and HERG missense mutations in Dutch long-QT families. | Hum Mutat | |
| RJ Jongbloed, AA Wilde, JL Geelen, P Doevendans, C Schaap, I Van Langen, JP van Tintelen, JM Cobben, GC Beaufort-Krol, JP Geraedts, HJ Smeets, | ||||||||
| Congenital long QT syndrome (cLQTS) is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncopes, seizure, or sudden death. LQTS can occur either as an autosomal dominant (Romano Ward) or as an autosomal recessive disorder (Jervell and Lange-Nielsen syndrome). Mutations in at least five genes have been associated with the LQTS. Four genes, encoding cardiac ion channels, have been identified. The most common forms of LQTS are due to mutations in the potassium-channel genes KCNQ1 and HERG. We have screened 24 Dutch LQTS families for mutations in KCNQ1 and HERG. Fourteen missense mutations were identified. Eight of these missense mutations were novel: three in KCNQ1 and five in HERG. Novel missense mutations in KCNQ1 were Y184S, S373P, and W392R and novel missense mutations in HERG were A558P, R582C, G604S, T613M, and F640L. The KCNQ1 mutation G189R and the HERG mutation R582C were detected in two families. The pathogenicity of the mutations was based on segregation in families, absence in control individuals, the nature of the amino acid substitution, and localization in the protein. Genotype-phenotype studies indicated that auditory stimuli as trigger of cardiac events differentiate LQTS2 and LQTS1. In LQTS1, exercise was the predominant trigger. In addition, a number of asymptomatic gene defect carriers were identified. Asymptomatic carriers are still at risk of the development of life-threatening arrhythmias, underlining the importance of DNA analyses for unequivocal diagnosis of patients with LQTS. | ||||||||
| 162 | 45.09 | 8747411 | 1996.10.24 | + | Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. | Pharmacogenetics | ||
| H Furuya, P Fernandez-Salguero, W Gregory, H Taber, A Steward, FJ Gonzalez, JR Idle, | ||||||||
| 163 | 44.98 | 11503010 | 2001.09.20 | + | + | Interindividual variability in sensitivity to warfarin--Nature or nurture? | Clin Pharmacol Ther | |
| R Loebstein, H Yonath, D Peleg, S Almog, M Rotenberg, A Lubetsky, J Roitelman, D Harats, H Halkin, D Ezra, | ||||||||
| BACKGROUND: Interindividual variability in responses to warfarin is attributed to dietary vitamin K, drug interactions, age, or genetic polymorphism in the cytochrome P4502C9 enzyme (CYP2C9) (allelic variants 2C9*2 and 2C9*3 ) linked with impaired metabolism of the potent enantiomere S-warfarin. PATIENTS AND METHODS: We quantified the relative effects of age and of simultaneously determined CYP2C9 genotype, plasma warfarin and vitamin K concentrations, and concurrent medications on warfarin maintenance doses in 156 patients at optimized stable anticoagulation. RESULTS: Allele frequencies for CYP2C9*1, CYP2C9*2, and CYP2C9*3 were 0.84, 0.10, and 0.06. Warfarin doses were 6.5 +/- 3.2, 5.2 +/- 2.4, and 3.3 +/- 2.0 mg/d in the 3 genotype groups (P < .0001). Warfarin doses decreased with age as follows: 7.7 +/- 3.7 versus 4.9 +/- 2.9 mg/d at < 50 years and >66 years (P < .001), mainly as a result of decreased plasma warfarin clearance (2.8 +/- 1.4 mL/min versus 1.9 +/- 0.8 mL/min; P < .001). Vitamin K (1.6 +/- 1.1 ng/mL) did not differ among the age or genotype groups. Patients >or=66 years old with the CYP2C9*3 allele required only 2.2 +/- 1.2 mg/d compared with 7.9 +/- 3.7 mg/d in those <or=65 years old bearing the CYP2C9*1 allele (P < .001). On multiple regression, warfarin maintenance doses were independently associated with plasma warfarin (reflecting its metabolic clearance) (r (2) = 0.26), age (possibly reflecting increased intrinsic sensitivity) (r (2) = 0.12), and genotype (reflecting S-warfarin levels) (r (2) = 0.10) but not with plasma vitamin K. CONCLUSIONS: At optimized steady state, individual sensitivity to warfarin is determined by CYP2C9 genotype and age with no effect of vitamin K. Prospective studies will determine the impact of these findings in clinical practice. | ||||||||
| 164 | 44.98 | 11908757 | 2002.04.09 | + | + | The predictive value of MDR1, CYP2C9, and CYP2C19 polymorphisms for phenytoin plasma levels. | Pharmacogenomics J | |
| R Kerb, AS Aynacioglu, J Brockmöller, R Schlagenhaufer, S Bauer, T Szekeres, A Hamwi, M Fritzer-Szekeres, C Baumgartner, HZ Ongen, P Güzelbey, I Roots, U Brinkmann, | ||||||||
| Phenytoin, an anticonvulsant, exhibits nonlinear pharmacokinetics with large interindividual differences. Because of its small therapeutic range with the risk of therapeutic failure or adverse drug effects in susceptible persons, therapeutic drug monitoring is frequently applied. The interindividual differences in dose response can partially be explained by known genetic polymorphisms in the metabolic enzyme CYP2C9 but a large deal of individual variability remains still unexplained. Part of this variability might be accounted for by variable uptake of phenytoin, which is a substrate of p-glycoprotein, encoded by the human MDR1 gene. We evaluated, whether phenytoin plasma levels correlate with a polymorphism in the MDR1 gene, C3435T, which is associated with intestinal PGP activity. Genotyping and analyses of plasma levels of phenytoin and metabolites in 96 healthy Turkish volunteers showed that the MDR1C > T3435 polymorphism affects phenytoin plasma levels (P = 0.064) and the metabolic ratio of p-HPPH vs phenytoin (MDR1*TT genotype, P = 0.026). The MDR1*CC genotype is more common in volunteers with low phenytoin levels (P < or = 0.001, chi2 test). A combined analysis of variable alleles of CYP2C9, 2C19 and MDR1 revealed that the number of mutant CYP2C9 alleles is a major determinant, the number of MDR1*T alleles further contributes to the prediction of phenytoin plasma levels and CYP2C19*2 does not explain individual variability. The regression equation that fitted the data best included the number of mutant CYP2C9 and MDR*T alleles as predictory variables and explained 15.4% of the variability of phenytoin data (r2 = 0.154, P = 0.0002). Furthermore, analysis of CYP2C9 and MDR1 genotypes in 35 phenytoin-treated patients recruited from therapeutic drug monitoring showed that combined CYP2C9 and MDR1 analysis has some predictive value not only in the controlled settings of a clinical trial, but also in the daily clinical practice. | ||||||||
| 165 | 44.97 | 7903915 | 1994.02.04 | + | + | Debrisoquin and mephenytoin hydroxylation phenotypes and CYP2D6 genotype in patients treated with neuroleptic and antidepressant agents. | Clin Pharmacol Ther | |
| A LLerena, AG Herraíz, J Cobaleda, I Johansson, ML Dahl, | ||||||||
| Debrisoquin and S-mephenytoin hydroxylation phenotypes were determined in 72 Spanish psychiatric patients treated with neuroleptic or antidepressant agents. One patient (1.4%) was classified as a poor metabolizer of S-mephenytoin. Between both neuroleptic- and antidepressant-treated patients, the distribution of the debrisoquin metabolic ratio was shifted toward higher values compared with 54 drug-free healthy subjects. Forty percent of patients treated with neuroleptics and 5% of patients treated with antidepressants were classified as poor metabolizers of debrisoquin. CYP2D6 genotype analysis in 36 neuroleptic-treated patients confirmed that the high metabolic ratios were attributable to inhibition of CYP2D6 and not to overrepresentation of subjects with poor metabolizer genotypes. In 48 selected Spanish drug-free subjects, CYP2D6 genotype predicted the phenotype with 95% accuracy. Neuroleptics and antidepressants interfere at therapeutic doses with phenotyping for CYP2D6 but not for S-mephenytoin hydroxylation capacity. In psychotropic-treated patients, genotyping provides a valuable tool for prediction of the CYP2D6 phenotype. | ||||||||
| 166 | 44.93 | 10663384 | 2000.03.02 | + | + | CYP2A6 genetic polymorphisms and liver microsomal coumarin and nicotine oxidation activities in Japanese and Caucasians. | Arch Toxicol | |
| K Inoue, H Yamazaki, T Shimada, | ||||||||
| Genotypes of CYP2A6, namely CYP2A6(*)1 (wild-type), CYP2A6(*)2, and CYP2A6(*)3, were examined in liver DNA of 39 Japanese and 43 Caucasians using two-step polymerase chain reaction (PCR) methods. We first amplified a DNA fragment (1725 bp) located between near middle of exon 1 and end of exon 4 of the CYP2A6 gene and further amplified using a forward primer 't' or 'mut' (middle of exon 3) and a reverse primer 'E3R' (middle of intron 3) for the detection of CYP2A6(*)2-genetic polymorphism. The 1725 bp fragment was also used for the amplification between exon 3 and near middle of intron 3 of the CYP2A6 gene and the fragment thus obtained digested with XcmI or DdeI to detect and confirm the CYP2A6(*)2- and CYP2A6(*)3-types, respectively. Only one DNA sample from a Japanese origin (J18) was not amplified by CYP2A6-specific primers; liver microsomes from this individual had very low activity of coumarin 7-hydroxylation and were devoid of protein(s) immunoreactive to anti-CYP2A6 antibody. Thus, this individual was suggested to be due to the gene deletion in CYP2A6. By analyzing the remaining 38 Japanese and 43 Caucasians, we found that there were no cases of CYP2A6(*)3-type polymorphism in the samples examined in this study, and no cases of CYP2A6(*)2-type polymorphism in the Japanese samples. Of Caucasians studied two individuals were classified into heterozygous CYP2A6(*)1/(*)2-type. Liver microsomal coumarin 7-hydroxylation activities in these two Caucasians were found to be lower than those of the other 41 Caucasians. Kinetic analysis showed that two CYP2A6(*)1/(*)2 individuals had a very low ratio of V(max) to K(m) for nicotine C-oxidation as well as coumarin 7-hydroxylation in liver microsomes, compared with those of homozygous CYP2A6(*)1-type. These results suggest that among 39 Japanese and 43 Caucasians examined one Japanese is classified to be CYP2A6 gene deletion and two Caucasians are heterozygous CYP2A6(*)1/(*)2-genotype. Thus the race-related differences in the occurrence of CYP2A6 genetic polymorphisms were supported. | ||||||||
| 167 | 44.91 | 15345706 | 2005.05.17 | + | + | Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. | Hum Mol Genet | |
| T Numakawa, Y Yagasaki, T Ishimoto, T Okada, T Suzuki, N Iwata, N Ozaki, T Taguchi, M Tatsumi, K Kamijima, RE Straub, DR Weinberger, H Kunugi, R Hashimoto, | ||||||||
| Genetic variation in dysbindin (DTNBP1: dystrobrevin-binding protein 1) has recently been shown to be associated with schizophrenia. The dysbindin gene is located at chromosome 6p22.3, one of the most promising susceptibility loci in schizophrenia linkage studies. We attempted to replicate this association in a Japanese sample of 670 patients with schizophrenia and 588 controls. We found a nominally significant association with schizophrenia for four single nucleotide polymorphisms and stronger evidence for association in a multi-marker haplotype analysis (P = 0.00028). We then explored functions of dysbindin protein in primary cortical neuronal culture. Overexpression of dysbindin induced the expression of two pre-synaptic proteins, SNAP25 and synapsin I, and increased extracellular basal glutamate levels and release of glutamate evoked by high potassium. Conversely, knockdown of endogenous dysbindin protein by small interfering RNA (siRNA) resulted in the reduction of pre-synaptic protein expression and glutamate release, suggesting that dysbindin might influence exocytotic glutamate release via upregulation of the molecules in pre-synaptic machinery. The overexpression of dysbindin increased phosphorylation of Akt protein and protected cortical neurons against neuronal death due to serum deprivation and these effects were blocked by LY294002, a phosphatidylinositol 3-kinase (PI3-kinase) inhibitor. SiRNA-mediated silencing of dysbindin protein diminished Akt phosphorylation and facilitated neuronal death induced by serum deprivation, suggesting that dysbindin promotes neuronal viability through PI3-kinase-Akt signaling. Genetic variants associated with impairments of these functions of dysbindin could play an important role in the pathogenesis of schizophrenia. | ||||||||
| 168 | 44.90 | 12700892 | 2004.01.08 | + | + | Haplotype analyses of cholesteryl ester transfer protein gene promoter: a clue to an unsolved mystery of TaqIB polymorphism. | J Mol Med | |
| H Lu, A Inazu, Y Moriyama, T Higashikata, MA Kawashiri, W Yu, Z Huang, T Okamura, H Mabuchi, | ||||||||
| Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to triglyceride-rich lipoproteins. TaqIB polymorphism (B2 allele) identified in intron 1 is associated with lower plasma CETP concentrations and higher HDL cholesterol levels and may play an antiatherogenic role in humans. However, its molecular mechanism remains unclear. To evaluate the association between the promoter polymorphisms and CETP/HDL cholesterol levels, ten novel and three previously reported polymorphisms located within 3.3 kb of the CETP gene promoter were investigated in a sample of 357 elderly Japanese men. All the promoter polymorphisms were in linkage disequilibrium with each other and with TaqIB. The -2505A allele, the "S" allele of the [gaaa](n) repeat ("S" denotes [gaaa](n)=329 bp and longer, "L" denotes >329 bp) and TaqIB2 allele were significantly associated with both lower plasma CETP concentrations and higher HDL cholesterol levels whereas -971G/A and -629A/C were significantly associated with CETP concentrations but not with HDL-C levels. The 12-polymorphism haplotypes consisting of -2804, -2505, [gaaa](n), -1930, -1674, -1129, -1046, -971, -875, -827, -629, and TaqIB were analyzed. These 12 polymorphisms generated eight main haplotypes, accounting for 86% of the observed haplotypes. The G/A/S/T/T/C/T/A/C/C/A/B2 haplotype was significantly associated with lower CETP concentrations (2.0+/-0.6 micro g/ml) and higher HDL cholesterol levels (55.1+/-12.7 mg/dl) than the other seven main haplotypes. The 5- and 3-polymorphism haplotype analyses consisting of -2505 and the [gaaa](n) repeat indicated the -2505C/A polymorphism might explain the variation in the CETP concentrations best, and the [gaaa](n) repeat and/or the -2505C/A polymorphism may independently determine the variation in HDL cholesterol levels, whereas the -629A/C and TaqIB polymorphisms were not instrumental in determining CETP concentrations as well as HDL cholesterol levels, although the latter has been frequently examined in many association studies. | ||||||||
| 169 | 44.89 | 11161380 | 2001.03.08 | + | + | The homeobox gene CDX2 in colorectal carcinoma: a genetic analysis. | Br J Cancer | |
| S Sivagnanasundaram, I Islam, I Talbot, F Drummond, JR Walters, YH Edwards, | ||||||||
| Accumulation of mutations in tumour suppressor genes and oncogenes has been proposed to underlie the initiation and progression of sporadic colorectal cancer (CRC). Evidence is accumulating to suggest that the caudal homeobox gene CDX2 is implicated in the pathogenesis of CRC. The CDX2 transcription factor is expressed in intestinal epithelium and is markedly down-regulated in colon tumours. Furthermore, Cdx2 heterozygous null mice develop multiple intestinal tumours. In this present study, we have investigated CDX2 as a potential candidate gene for sporadic CRC by a thorough search of all exons and exon/intron boundaries for DNA polymorphisms and rare variants in a panel of CRC tumours. 6 polymorphisms were identified and the haplotypes determined. In addition two rare variants were found, one of which was only identified in DNA from a CRC case. Loss of heterozygosity was observed in 3 out of 28 informative CRC cases. A possible association between particular haplotypes and tumour progression was also suggested by the data. In addition a preliminary analysis of the relative expression of CDX2 alleles in tumour/normal tissue suggested some variation in the levels, however further analysis is required before any conclusions can be drawn. While CDX2 mutations predisposing to sporadic CRC have not been identified, this study has established that loss of CDX2 contributes towards the progression of some sporadic CRC tumours. | ||||||||
| 170 | 44.89 | 9549339 | 1998.06.22 | + | + | [Individualization of drug therapy and pharmacogenetics] | Nippon Rinsho | |
| I Yamamoto, J Azuma, | ||||||||
| This brief review discusses the relationship between genetic polymorphism of drug metabolizing enzyme and drug's safety and efficacy. When elimination occurs via a single metabolic pathway, individual differences in metabolic rates can lead to large differences in drug and metabolite concentrations in the blood. Genetic polymorphism leads to subpopulation of patients with decreased, absent or even increased activities of certain reactions (e.g., CYP2C19, CYP2D6, CYP2C9, N-acetyltransferase, thiopurine methyltransferase polymorphism). The consequences of a genetic polymorphism include not only altered kinetics of specific drug substrate but idiosyncratic adverse drug reactions. Having these information will aid in determining dosage of certain medications to the patients with an inherited abnormality of drug metabolizing enzyme. Pharmacogenetics already has influenced therapeutics. | ||||||||
| 171 | 44.85 | 9154246 | 1997.06.09 | + | + | A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. | Mol Psychiatry | |
| DA Collier, G Stöber, T Li, A Heils, M Catalano, D Di Bella, MJ Arranz, RM Murray, HP Vallada, D Bengel, CR Müller, GW Roberts, E Smeraldi, G Kirov, P Sham, KP Lesch, | ||||||||
| The serotonin transporter (5-HTT) is a candidate locus for aetiological involvement in affective disorders. Biochemical studies in suicides and depressed patients suggest that 5-HT uptake function is frequently reduced in affective illness. Furthermore, 5-HTT is targeted by widely used antidepressant drugs such as fluoxetine. We have performed an association study of a short variant of the 5-HTT-linked polymorphic region (5-HTTLPR), which restricts transcriptional activity of the 5-HTT promoter leading to low functional expression of the 5-HTT, in 454 patients with bipolar or unipolar affective disorder and 570 controls, derived from three European Centres (London, Milan and Würzburg). In all three centres, the frequency of the low activity allele was higher in patients than in controls (50% vs 45% in London, 45% vs 43% in Milan, 47% vs 40% in Würzburg). Although these differences were not individually significant, a stratified analysis of all three samples gave a significant overall odds ratio of 1.23 (95% confidence interval 1.02-1.49, P = 0.03). The excess of the homozygous low-activity genotype among the patients was even greater (odds ratio 1.53, 95% confidence interval 1.04-2.23, P = 0.02), suggesting partial recessively of the low-activity allele. Given the functional role of 5-HTT, our findings suggest that 5-HTTLPR-dependent variation in functional 5-HTT expression is a potential genetic susceptibility factor for affective disorders. If this finding is replicated, further work on genetic variants with low 5-HTT activity may facilitate the differential diagnosis of affective disorders, the assessment of suicidal behaviour, and the prediction of good clinical response to antidepressants. | ||||||||
| 172 | 44.83 | 8081414 | 1994.10.13 | + | + | The cytochrome P450 CYP2D6 allelic variant CYP2D6J and related polymorphisms in a European population. | Pharmacogenetics | |
| M Armstrong, K Fairbrother, JR Idle, AK Daly, | ||||||||
| DNA from two subjects showing anomalous CYP2D6 phenotype-genotype relationships was analysed for the presence of new CYP2D6 mutations by single strand conformational polymorphism (SSCP) analysis. One of these subjects was homozygous for polymorphisms in exon 1 and exon 9 previously detected in Oriental populations and termed the CYP2D6J allele. The frequency of these polymorphisms and their effect on phenotype was investigated in a European population with a small Chinese population as a control group. Subjects homozygous for both polymorphisms showed impaired metabolism of debrisoquine whereas subjects with the exon 9 mutation only appeared to show similar metabolism to the wild-type. The CYP2D6J allele frequency was 0.05 in the European group compared with 0.47 for the Chinese group. The relationship between the CYP2D6J allele and the exon 9 polymorphism and the presence of insertions upstream of CYP2D6 detectable by RFLP analysis with Xba I was investigated. In the Chinese group the insertion appeared to be associated with the CYP2D6J allele but in the European group no association was detected. Subjects homozygous for the CYP2D6J allele appear to show a similar debrisoquine phenotype to those heterozygous for CYP2D6-inactivating mutations but the exon 9 polymorphism or the presence of an upstream insertion without an associated CYP2D6B or CYP2D6J allele does not appear to affect enzyme activity. | ||||||||
| 173 | 44.73 | 10444342 | 1999.09.22 | + | + | A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. | Mol Genet Metab | |
| A Wilson, R Platt, Q Wu, D Leclerc, B Christensen, H Yang, RA Gravel, R Rozen, | ||||||||
| Impairment of folate and cobalamin (vitamin B(12)) metabolism has been observed in families with neural tube defects (NTDs). Genetic variants of enzymes in the homocysteine remethylation pathway might act as predisposing factors contributing to NTD risk. The first polymorphism linked to increased NTD risk was the 677C-->T mutation in methylenetetrahydrofolate reductase (MTHFR). We now report a polymorphism in methionine synthase reductase (MTRR), the enzyme that activates cobalamin-dependent methionine synthase. This polymorphorism, 66A-->G (I22M), has an allele frequency of 0.51 and increases NTD risk when cobalamin status is low or when the MTHFR mutant genotype is present. Genotypes and cobalamin status were assessed in 56 patients with spina bifida, 58 mothers of patients, 97 control children, and 89 mothers of controls. Cases and case mothers were almost twice as likely to possess the homozygous mutant genotype when compared to controls, but this difference was not statistically significant. However, when combined with low levels of cobalamin, the risk for mothers increased nearly five times (odds ratio (OR) = 4.8, 95% CI 1.5-15.8); the OR for children with this combination was 2.5 (95% CI 0.63-9.7). In the presence of combined MTHFR and MTRR homozygous mutant genotypes, children and mothers had a fourfold and threefold increase in risk, respectively (OR = 4.1, 95% CI 1.0-16.4; and OR = 2.9, 95% CI 0.58-14.8). This study provides the first genetic link between vitamin B(12) deficiency and NTDs and supports the multifactorial origins of these common birth defects. Investigation of this polymorphism in other disorders associated with altered homocysteine metabolism, such as vascular disease, is clearly warranted. | ||||||||
| 174 | 44.68 | 9630825 | 1998.07.08 | + | + | Metabolism of warfarin enantiomers in Japanese patients with heart disease having different CYP2C9 and CYP2C19 genotypes. | Clin Pharmacol Ther | |
| H Takahashi, T Kashima, Y Nomizo, N Muramoto, T Shimizu, K Nasu, T Kubota, S Kimura, H Echizen, | ||||||||
| OBJECTIVE: To determine whether genetic polymorphism of cytochrome P450 (CYP) 2C9 affects the in vivo metabolism of warfarin enantiomers. METHODS: Eighty-six Japanese patients heart disease who were given warfarin participated in the study. Plasma unbound concentrations of warfarin enantiomers and urinary (S)-7-hydroxywarfarin concentrations were measured by means of a chiral HPLC and ultrafiltration technique to calculate the unbound oral clearance (CLpo,u) for the enantiomers and the formation clearance (CLm) for (S)-warfarin 7-hydroxylation. Genotyping for CYP2C9 (the wild type [wt], Arg144/Cys, and I1e359/Leu) and for CYP2C19 (wt, ml, and m2) was performed with a polymerase chain reaction method. RESULTS: Three patients were heterozygous for the CYP2C9 Leu359 mutation but none were homozygous for the mutation (the allele frequency of 0.017). None had a CYP2C9 Cys144 allele. The medians for (S)-warfarin CLpo,u and its 7-hydroxylation CLm obtained from heterozygotes of CYP2C9 Leu359 were significantly less than those obtained from homozygotes of the wt allele, as follows: 234 ml/min (range, 156 to 269 ml/min) versus 632 ml/min (range, 180 to 2070 ml/min) (p < 0.001) and 0.20 ml/min (range, 0.05 to 0.77 ml/min) versus 0.80 ml/min (range, 0.05 to 14.9 ml/min) (p < 0.05), respectively. In contrast, no difference was observed in (R)-warfarin CLpo,u between the groups. The allele frequencies for CYP2C19 m1 and CYP2C19 m2 were 0.26 and 0.14, respectively, indicating 15% of patients were genotypically poor metabolizers of CYP2C19. No difference in CLpo,u for warfarin enantiomers was observed between the assumed CYP2C19 phenotypes. CONCLUSION: Heterozygotes for CYP2C9 I1e359/Leu allele have reduced in vivo metabolism of (S)-warfarin but not (R)-warfarin. Because (S)-warfarin has a greater anticoagulant potency than its (R)-congener, the genetic polymorphism of CYP2C9 may partly account for the large interpatient variability in therapeutic dosages of warfarin. | ||||||||
| 175 | 44.68 | 11404819 | 2001.08.02 | + | + | Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. | Am J Hum Genet | |
| MD Ritchie, LW Hahn, N Roodi, LR Bailey, WD Dupont, FF Parl, JH Moore, | ||||||||
| One of the greatest challenges facing human geneticists is the identification and characterization of susceptibility genes for common complex multifactorial human diseases. This challenge is partly due to the limitations of parametric-statistical methods for detection of gene effects that are dependent solely or partially on interactions with other genes and with environmental exposures. We introduce multifactor-dimensionality reduction (MDR) as a method for reducing the dimensionality of multilocus information, to improve the identification of polymorphism combinations associated with disease risk. The MDR method is nonparametric (i.e., no hypothesis about the value of a statistical parameter is made), is model-free (i.e., it assumes no particular inheritance model), and is directly applicable to case-control and discordant-sib-pair studies. Using simulated case-control data, we demonstrate that MDR has reasonable power to identify interactions among two or more loci in relatively small samples. When it was applied to a sporadic breast cancer case-control data set, in the absence of any statistically significant independent main effects, MDR identified a statistically significant high-order interaction among four polymorphisms from three different estrogen-metabolism genes. To our knowledge, this is the first report of a four-locus interaction associated with a common complex multifactorial disease. | ||||||||
| 176 | 44.64 | 11699613 | 2002.04.26 | + | + | Comparison of the kinetic disposition of and serum gastrin change by lansoprazole versus rabeprazole during an 8-day dosing scheme in relation to CYP2C19 polymorphism. | Eur J Clin Pharmacol | |
| I Ieiri, Y Kishimoto, H Okochi, K Momiyama, T Morita, M Kitano, T Morisawa, Y Fukushima, K Nakagawa, J Hasegawa, K Otsubo, T Ishizaki, | ||||||||
| BACKGROUND: Little is known about differences in the disposition kinetics and pharmacological effects on gastrin levels between lansoprazole and rabeprazole given in a repeated dosing scheme with respect to the polymorphic CYP2C19. AIM: To provide preliminary information that should be considered when prescribing proton-pump inhibitors (PPIs) for the treatment of acid-related diseases with reference to the CYP2C/9 genotypic status. METHODS: Helicobacter pylori-negative healthy volunteers were divided into the following three groups (n = 5 each) on the basis of genotyping for CYP2C19: homozygous (hmEMs) and heterozygous extensive metabolizers (htEMs), and poor metabolizers (PMs). All received once-daily 30-mg doses of lansoprazole or 10-mg doses of rabeprazole during an 8-day course in a crossover manner. RESULTS: The relative values for the area under the serum concentration-time curve (AUC) of lansoprazole and rabeprazole in the hmEMs, htEMs, and PMs after the final doses were 1:1.7:3.9 and 1:1.7:3.8, respectively. The relative AUCs of gastrin in the hmEMs, htEMs, and PMs were 1.6:2.6:3.1 for lansoprazole and 1.6:2.6:2.9 for rabeprazole, respectively. CONCLUSION: The disposition kinetic behavior of the two PPIs is co-segregated with CYP2C19. The magnitude of CYP2C19-dependent drug availability in the systemic circulation and resulting gastrin response appears to be fairly similar between the two drugs within the same CYP2C19 genotypic groups after a multiple-dosing regimen. | ||||||||
| 177 | 44.64 | 8101460 | 1993.08.26 | + | + | Debrisoquine oxidation polymorphism: phenotypic consequences of a 3-base-pair deletion in exon 5 of the CYP2D6 gene. | Pharmacogenetics | |
| F Broly, UA Meyer, | ||||||||
| A mutant allele of the CYP2D6 gene (CYP2D6* C) characterized by a 3-base-pair deletion in exon 5 (mutation D6-C) and carried by a Xba I 29 kb restriction fragment (haplotype 29-C) was previously presumed to be associated with the debrisoquine poor metabolizer phenotype on the basis of in vitro enzymatic criteria. In order to determine whether D6-C was related to a deficient CYP2D6 activity in vivo, we first analyzed the CYP2D6 gene in the family of a carrier of the haplotype 29-C by combining Xba I-restriction-fragment-length polymorphism analysis and specific CYP2D6 mutation detection by polymerase chain reaction assays. Moreover, each member of the family was phenotyped using debrisoquine as probe drug. Secondly, we used polymerase chain reaction assays to test for the CYP2D6* C mutation DNA samples from 146 unrelated healthy volunteers with the extensive metabolizer phenotype and previously identified as heterozygous carrier of one of the haplotypes known to be associated with the poor metabolizer phenotype. All family members were extensive metabolizers and three were compound heterozygotes for the haplotype 29-C and a 11.5 kb haplotype that has been shown to lack the entire CYP2D6 gene. In addition, two extensive metabolizer individuals among the 146 tested for were compound heterozygotes for the haplotype 29-C and a 29 kb haplotype carrying the defective CYP2D68* B allele (haplotype 29-B).(ABSTRACT TRUNCATED AT 250 WORDS) | ||||||||
| 178 | 44.64 | 12874455 | 2004.09.09 | + | + | Identification of a common risk haplotype for diabetic nephropathy at the protein kinase C-beta1 (PRKCB1) gene locus. | J Am Soc Nephrol | |
| S Araki, DP Ng, B Krolewski, L Wyrwicz, JJ Rogus, L Canani, Y Makita, M Haneda, JH Warram, AS Krolewski, | ||||||||
| Abnormal activation of protein kinase C-beta isoforms in the diabetic state has been implicated in the development of diabetic nephropathy. It is thus plausible that DNA sequence differences in the protein kinase C-beta1 gene (PRKCB1), which encodes both betaI and betaII isoforms, may influence susceptibility to nephropathy. Nine single-nucleotide polymorphisms (SNP) in PRKCB1 were tested for association with diabetic nephropathy in type I diabetes mellitus, by using both case-control and family-study designs. Allele and genotype distributions of two SNP in the promoter (--1504C/T and --546C/G) differed significantly between case patients and control patients (P < 0.05). These associations were particularly strong with diabetes mellitus duration of <24 yr (P = 0.002). The risk of diabetic nephropathy was higher among carriers of the T allele of the --1504C/T SNP, compared with noncarriers (odds ratio, 2.54; 95% confidence interval, 1.39 to 4.62), and among carriers of the G allele of the --546C/G SNP (odds ratio, 2.45; 95% confidence interval, 1.37 to 4.38). Among individuals with diabetes mellitus duration of >/==" BORDER="0">24 yr, these two SNP were not associated with diabetic nephropathy. These positive findings were confirmed by using the family-based transmission disequilibrium test. The T-G haplotype, with both risk alleles, was transmitted more frequently than expected from heterozygous parents to offspring who developed diabetic nephropathy during the first 24 yr of diabetes mellitus. It is concluded that DNA sequence differences in the promoter of PRKCB1 contribute to diabetic nephropathy susceptibility in type I diabetes mellitus. | ||||||||
| 179 | 44.55 | 11149425 | 2001.01.25 | + | + | Frequency of BRCA1 and BRCA2 germline mutations in Japanese breast cancer families. | Int J Cancer | |
| N Ikeda, Y Miyoshi, K Yoneda, E Shiba, Y Sekihara, M Kinoshita, S Noguchi, | ||||||||
| The purpose of this investigation is to study the frequency of BRCA1 and BRCA2 germline mutations in Japanese breast cancer families. Mutation analysis of BRCA1 and BRCA2 by SSCP was conducted on the 113 breast cancer patients (probands) with at least 1 breast cancer (site-specific breast cancer families, n = 101) or 1 ovarian cancer (breast/ovarian cancer families, n = 12) patient in their first-degree relatives. Fifteen deleterious mutations (13.3%), including 8 nonsense and 7 frameshift mutations, were identified in BRCA1, and 21 deleterious mutations (18.6%), including 8 nonsense, 12 frameshift and 1 splice-site mutations, were identified in BRCA2. In site-specific breast cancer families, mutation frequency of BRCA1 or BRCA2 was high in families with 3 or more breast cancer patients (36%, 9/25), early onset (40 < or = years old) breast cancer patients (38%, 19/50) or bilateral breast cancer patients (40%, 6/15). In breast/ovarian cancer families, mutations of BRCA1 (58.3%, n = 7), but not BRCA2 (0%, n = 0), were observed. BRCA1 codon 63 (TTA to TAA) nonsense mutation and BRCA2 frameshift mutation (5802 del AATT) were observed in 4 and 7 independent families, respectively. Haplotype analysis has suggested that carriers of each of these mutations have common ancestors. These results demonstrate that family profiles are important determinants of risk for carrying a BRCA1 or BRCA2 mutation and that cumulative frequency of BRCA1 and BRCA2 mutations in Japanese breast cancer families (31.9%) is within the range observed in Caucasian breast cancer families. Presence of Japanese founder mutations has also been suggested. | ||||||||
| 180 | 44.55 | 12618310 | 2003.06.10 | + | + | Cancer pharmacogenomics: current and future applications. | Biochim Biophys Acta | |
| JW Watters, HL McLeod, | ||||||||
| Heterogeneity in patient response to chemotherapy is consistently observed across patient populations. Pharmacogenomics is the study of inherited differences in interindividual drug disposition and effects, with the goal of selecting the optimal drug therapy and dosage for each patient. Pharmacogenomics is especially important for oncology, as severe systemic toxicity and unpredictable efficacy are hallmarks of cancer therapies. In addition, genetic polymorphisms in drug metabolizing enzymes and other molecules are responsible for much of the interindividual differences in the efficacy and toxicity of many chemotherapy agents. This review will discuss clinically relevant examples of gene polymorphisms that influence the outcome of cancer therapy, and whole-genome expression studies using microarray technology that have shown tremendous potential for benefiting cancer pharmacogenomics. The power and utility of the mouse as an experimental system for pharmacogenomic discovery will also be discussed in the context of cancer therapy. | ||||||||
| 181 | 44.54 | 8287064 | 1994.02.22 | + | + | Evidence for a new variant CYP2D6 allele CYP2D6J in a Japanese population associated with lower in vivo rates of sparteine metabolism. | Pharmacogenetics | |
| H Yokota, S Tamura, H Furuya, S Kimura, M Watanabe, I Kanazawa, I Kondo, FJ Gonzalez, | ||||||||
| A group of Japanese subjects were phenotyped for CYP2D6 activity by administration of sparteine and determination of urine metabolic ratios (MR). The CYP2D6 alleles from two subjects having a high MR, characteristic of slower rates of sparteine metabolism, were cloned in lambda EMBL3 and subjected to sequence analysis. One individual possessed a CYP2D6B allele, typically found in Caucasians, that is inactive due to an altered 3' splice recognition site and other potentially disruptive mutations. The second allele from this individual was identical to the wild type normal Caucasian CYP2D6 allele except for C188T and G4268C base differences in exons 1 and 9, respectively, that result in P34S and S486T amino acid substitutions. This allele was designated CYP2D6J. The second individual possessed two CYP2D6J alleles. PCR assays were performed to detect this allele and other alleles from a group of subjects exhibiting low rates of sparteine metabolism, i.e. with MRs > 1.5. Eleven CYP2D6J alleles were detected in 14 subjects exhibiting low rates of metabolism and including four individuals who were homozygous for this variant and had very low rates of sparteine metabolism (MRs > 2.5). In contrast, only two CYP2D6J alleles were found in 14 subjects having MRs of < 1.0. These data suggest that CYP2D6J encodes an enzyme having lower rates of sparteine metabolism. | ||||||||
| 182 | 44.54 | 12571232 | 2003.05.22 | + | + | A novel distal enhancer module regulated by pregnane X receptor/constitutive androstane receptor is essential for the maximal induction of CYP2B6 gene expression. | J Biol Chem | |
| H Wang, S Faucette, T Sueyoshi, R Moore, S Ferguson, M Negishi, EL LeCluyse, | ||||||||
| CYP2B6 plays an important role in the metabolism of a variety of structurally unrelated xenobiotics, including the anticancer drugs cyclophosphamide and ifosfamide. Previous studies have shown that the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are involved in the transcriptional regulation of CYP2B genes through the phenobarbital-responsive enhancer module (PBREM). However, for human CYP2B6 the relatively weak response of the PBREM to PXR and CAR activation in transfection assays fails to describe the potent induction observed in primary human hepatocyte cultures. In this report, a novel nuclear receptor response module located -8.5 kilobases upstream from the CYP2B6 encoding region is described. Several potential PXR/CAR binding motifs were identified within the distal regulatory cluster. In electrophoretic mobility shift assays, one DR4 motif showed the strongest binding to both PXR and CAR. Transient transfection assays in HepG2 cells demonstrated that the novel distal response cluster could be activated by PXR and CAR. In primary human hepatocytes, both PBREM and the distal responsive element were activated individually by endogenous nuclear receptors upon exposure to prototypical inducers. However, in both HepG2 cells and primary human hepatocytes maximal reporter activation was observed in a construct containing both PBREM and the distal responsive element. In mouse tail-vein injection experiments, a construct containing both the distal responsive element and the proximal PBREM exhibited a strong synergistic expression in phenobarbital-treated mice. These results show that a novel xenobiotic-responsive enhancer module in the distal region of the CYP2B6 promoter (CYP2B6-XREM) together with the PBREM mediates optimal drug-induced expression of CYP2B6. | ||||||||
| 183 | 44.53 | 7901140 | 1993.12.21 | + | + | DNA haplotype dependency of debrisoquine 4-hydroxylase (CYP2D6) expression among extensive metabolisers. | Hum Genet | |
| C Mura, S Panserat, M Vincent-Viry, MM Galteau, E Jacqz-Aigrain, R Krishnamoorthy, | ||||||||
| Deficient debrisoquine/sparteine type oxidation is inherited as an autosomal recessive trait. Of all Caucasians, 5-10% are poor metabolisers, due to the absence of cytochrome P4502D6. Extensive metabolisers (EMs) exhibit highly variable metabolic activity. We investigated the relationship between CYP2D6 activity and genotypes of the CYP2D locus in a large set of French Caucasian families. Genotypes concern both common mutations affecting the enzyme activity and linked BamHI polymorphisms of the locus. We found, like other authors, that in EMs part of the heterogeneity is explained by a subgroup of individuals heterozygous for a mutant allele. However, a second level of heterogeneity was detected among individuals not carrying mutations, and this was related to a polymorphic BamHI-defined DNA haplotype. Different combinations of haplotypes are associated with differences in CYP2D6 metabolic activity. This finding might help to clarify the conflicting data on the relation between CYP2D6 activity and susceptibility to lung cancer. | ||||||||
| 184 | 44.48 | 11156223 | 2001.04.19 | + | + | Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. | Clin Cancer Res | |
| AB van Kuilenburg, J Haasjes, DJ Richel, L Zoetekouw, H Van Lenthe, RA De Abreu, JG Maring, P Vreken, AH van Gennip, | ||||||||
| Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU), and it is suggested that patients with a partial deficiency of this enzyme are at risk for developing a severe 5FU-associated toxicity. To evaluate the importance of this specific type of inborn error of pyrimidine metabolism in the etiology of 5FU toxicity, an analysis of the DPD activity, the DPD gene, and the clinical presentation of patients suffering from severe toxicity after the administration of 5FU was performed. Our study demonstrated that in 59% of the cases, a decreased DPD activity could be detected in peripheral blood mononuclear cells. It was observed that 55% of patients with a decreased DPD activity suffered from grade IV neutropenia compared with 13% of patients with a normal DPD activity (P = 0.01). Furthermore, the onset of toxicity occurred, on average, twice as fast in patients with low DPD activity as compared with patients with a normal DPD activity (10.0 +/- 7.6 versus 19.1 +/- 15.3 days; P < 0.05). Analysis of the DPD gene of 14 patients with a reduced DPD activity revealed the presence of mutations in 11 of 14 patients, with the splice site mutation IVS14+1G-->A being the most abundant one (6 of 14 patients; 43%). Two novel missense mutations 496A-->G (M166V) and 2846A-->T (D949V) were detected in exon 6 and exon 22, respectively. Our results demonstrated that at least 57% (8 of 14) of the patients with a reduced DPD activity have a molecular basis for their deficient phenotype. | ||||||||
| 185 | 44.42 | 10383153 | 1999.07.19 | + | + | Candidate genetic modifiers of individual susceptibility to renal cell carcinoma: a study of polymorphic human xenobiotic-metabolizing enzymes. | Cancer Res | |
| S Longuemaux, C Deloménie, C Gallou, A Méjean, M Vincent-Viry, R Bouvier, D Droz, R Krishnamoorthy, MM Galteau, C Junien, C Béroud, JM Dupret, | ||||||||
| The steady increase in sporadic renal cell carcinoma (RCC) observed in industrialized countries supports the notion that certain carcinogens present in the environment (tobacco smoke, drugs, pollutants, and dietary constituents) may affect the occurrence of RCC. Many of the enzymes dealing with such environmental factors are polymorphic and may, therefore, confer variable susceptibility to RCC. This case-control study was designed to test for an association between genetic polymorphism of enzymes involved in xenobiotic metabolism and the risk of sporadic RCC. Genomic DNA was obtained from 173 patients with RCC and 211 controls of Caucasian origin. We used PCR-RFLP to investigate polymorphism for the most common alleles at two cytochrome-P450 mono-oxygenases (CYP1A1 and CYP2D6), one NAD[P]H:quinone oxidoreductase (NQO1), three glutathione S-transferases (GSTM1, GSTT1, and GSTP1), and one N-acetyltransferase (NAT2) loci. The CYP1A1 (m) "variant" genotype, which contains at least one copy of the CYP1A1 variant alleles, was found to be associated with a 2.1-fold [95% confidence interval (CI), 1.1-3.9] increase in the risk of RCC. There was also a higher risk of RCC for subjects with the CYP1A1 (m) variant genotype combined with any of the following genotypes: GSTT1 (+) "active" [odds ratio (OR), 2.3; 95% CI, 1.2-4.5], GSTP1 (m) variant (OR, 2.4; 95% CI, 1.0-5.4), or NAT2 (-) "slow acetylator" (OR, 2.5; 95% CI, 1.1-5.5). A significant association was also found for the GSTM1 (-) "null" and GSTP1 (m) genotypes combined with either NAT2 (-) (OR, 2.6; 95% CI, 1.2-5.8) or CYP1A1 (m) (OR, 3.5; 95% CI, 1.1-11.2). The CYP2D6 (-) "poor metabolizer " and the NQO1 (-) "defective" genotypes were not clearly associated with a higher risk of RCC. Our data demonstrate for the first time a significant association between a group of pharmacogenetic polymorphisms and RCC risk. These positive findings suggest that interindividual variation in the metabolic pathways involved in the functionalization and detoxification of specific xenobiotics is an important susceptibility factor for RCC in Caucasians. | ||||||||
| 186 | 44.40 | 14749922 | 2004.04.27 | + | + | Leukotriene-related gene polymorphisms in ASA-intolerant asthma: an association with a haplotype of 5-lipoxygenase. | Hum Genet | |
| JH Choi, HS Park, HB Oh, JH Lee, YJ Suh, CS Park, HD Shin, | ||||||||
| A recent study has demonstrated the possible involvement of a leukotriene C4 synthase (LTC4S) gene polymorphism in ASA-intolerant asthma (AIA) in a Polish population, whereas no significant association was noted in other populations. To investigate the role of genetic polymorphism in AIA development, we screened single nucleotide polymorphisms (SNPs) of the key enzymes involved in arachidonate metabolism, and the cysteinyl leukotriene receptor 1 (CYSLTR1) in a large Korean population with AIA: 93 AIA and 181 ASA-tolerant asthma (ATA) patients, and 123 normal controls. The single-base extension method was used to genotype SNPs in 5-lipoxygenase (ALOX5, -1708G-->A, 21C-->T, 270G-->A, 1728G-->A), ALOX5-activating protein (ALOX5AP, 218A-->G), prostaglandin-endoperoxide synthase 2 (PTGS2, COX2, -162C-->G, 10T-->G, R228H, V511A), LTC4S (-444A-->C), and CYSLTR1 (927T-->C). Haplotype analyses were undertaken for the SNPs in ALOX5. No significant differences in allele and genotype frequencies of single SNPs were observed between the patient groups ( P>0.05). However, the frequency of the ALOX5-ht1[G-C-G-A] haplotype in the AIA group was significantly higher than its frequency in the ATA group with a probability ( P) of 0.01, odds ratio (OR) of 5.0, and 95% confidence interval (95%CI) of 1.54-17.9, and in the normal controls ( P=0.03, OR=4.5, 95%CI=1.1-18.4), by using a dominant model. These results suggest a lack of association between the ALOX5AP, PTGS2, LTC4S, and CYSLTR1 gene polymorphisms and the AIA phenotype in the Korean population. However, the possible involvement of ALOX5-ht1[G-C-G-A] in AIA development is suggested. | ||||||||
| 187 | 44.39 | 15635701 | 2005.03.14 | + | + | Identification and characterization of human NR4A2 polymorphisms in attention deficit hyperactivity disorder. | Am J Med Genet B Neuropsychiatr Genet | |
| KM Smith, L Bauer, M Fischer, R Barkley, BA Navia, | ||||||||
| Attention deficit hyperactivity disorder (ADHD) is a highly heritable and common disorder thought to arise, in part, from alterations in dopamine function. NR4A2, or Nurr1, is an orphan nuclear receptor implicated in the development of dopaminergic cells of the ventral tegmental area (VTA) and the substantia nigra (SN). Dopaminergic cells of the VTA provide innervation to the prefrontal cortex, believed to be of major importance in the etiology of ADHD, suggesting that NR4A2 is a potential candidate gene for ADHD susceptibility. This study aimed to identify polymorphisms in NR4A2 and test their association to ADHD. Database analysis revealed a CA repeat polymorphism in the 3' UTR of NR4A2 that was confirmed by PCR. SSCP screening revealed a common DeltaC polymorphism, 254 bp 5' to the transcriptional start site. These polymorphisms were tested for an association with ADHD in both a case control study of individuals from the Milwaukee Longitudinal Study of ADHD (103 cases and 66 controls), and in 35 families composed of trios or affected sib pairs (ASP) with ADHD. Functional effects of the promoter polymorphism were tested in vitro. The non-deleted allele was significantly more active in undifferentiated SK-N-MC cells compared to differentiated SK-N-MC and HeLa cells while a trend for increased activity for the DeltaC allele was observed in undifferentiated SK-N-MC cells. Identification of these polymorphisms may aid future candidate gene studies in disorders with altered dopamine signaling, such as schizophrenia Parkinson's disease and ADHD. | ||||||||
| 188 | 44.38 | 15801936 | 2005.08.01 | + | + | Pharmacogenetic profiling across the irinotecan pathway in Asian patients with cancer. | Br J Clin Pharmacol | |
| Q Zhou, A Sparreboom, EH Tan, YB Cheung, A Lee, D Poon, EJ Lee, B Chowbay, | ||||||||
| AIMS: The aim of this exploratory study was to investigate associations between irinotecan pharmacokinetic parameters and allelic variants in genes encoding for drug transporters and drug metabolizing enzymes that are involved in irinotecan disposition in Asian patients with cancer. METHODS: Irinotecan was administered at 100 mg m(-2) over 90 min on a weekly schedule to 29 nasopharyngeal carcinoma patients and pharmacokinetic analysis was performed during the first cycle. All patients were genotyped for allelic variants in genes encoding drug metabolizing enzymes (CYP3A4, CYP3A5, UGT1A1) and drug transporters (ABCB1, ABCC2 and ABCG2) that are involved in irinotecan disposition. RESULTS: Of the six candidate genes that were analyzed, 11 genetic variants were found. Significant genotypic-phenotypic associations were apparent only for transporter genes. The C(max) of irinotecan was significantly lower in patients carrying the CC genotype at exon 26 of the ABCB1 gene compared with those harbouring at least one variant allele (P = 0.047). Patients harbouring the wild type ABCG2 CTCA genotype were associated with significantly higher values for relative extent of conversion (REC) of irinotecan to SN-38 compared with patients carrying at least one deletion CTCA allele (P = 0.019). CONCLUSIONS: The present exploratory study shows that genetic polymorphisms in drug transporter genes, particularly in ABCB1 and ABCG2 genes, may be important in influencing the pharmacokinetics of irinotecan and its metabolites. The predictive value of the identified allelic variants in the ABCG2 and ABCB1 genes on irinotecan disposition should be further investigated in a larger patient population as well as in other ethnic populations. | ||||||||
| 189 | 44.38 | 11594341 | 2002.01.07 | + | Mutation detection in long QT syndrome: a comprehensive set of primers and PCR conditions. | J Med Genet | ||
| P Syrris, A Murray, ND Carter, WM McKenna, S Jeffery, | ||||||||
| 190 | 44.36 | 8845864 | 1996.10.21 | + | + | Interaction of human liver cytochromes P450 in vitro with LY307640, a gastric proton pump inhibitor. | Pharmacogenetics | |
| M VandenBranden, BJ Ring, SN Binkley, SA Wrighton, | ||||||||
| The interactions in vitro of LY307640 with the cytochromes P450 (P450s) were studied using human liver microsomes, specific inhibitors of the P450s, and cDNA expressed enzymes. The kinetics of formation of the two major oxidative metabolites, desmethyl LY307640 and LY307640 sulfone, were determined using two human liver microsomal samples. The kinetic data indicated that high and low affinity sites were present for the production of both metabolites of LY307640. The Km(apparent) and Vmax(apparent) for desmethyl LY307640 formation by microsomes from human liver E (HL-E) for the high affinity site were 18.8 +/- 4.4 microM and 402 +/- 52 pmol product/min/mg protein. The high affinity site Km(apparent) and Vmax(apparent) for LY307640 sulfone formation by microsomes from HL-E were 4.4 +/- 2.1 microM and 81.8 +/- 18 pmol product/min/mg protein. The rates of desmethyl LY307640 and LY307640 sulfone formation by the high affinity site were determined using 14 human liver microsomal samples characterized for P450 marker catalytic activities and immunoquantified levels of the P450s. Rates of formation of desmethyl LY307640 significantly correlated with the immunoquantified levels of CYP 2C19 and the ability of the microsomes to 4'-hydroxylate S-mephenytoin. LY307640 sulfone formation significantly correlated with the immunoquantified levels of CYP 3A and the ability of the microsomes to 1'-hydroxylate midazolam. Inhibition studies and use of expressed cytochrome P450 systems confirmed the correlation data demonstrating that CYP 2C19 catalyzed the formation of desmethyl LY307640 and CYP 3A and catalyzed LY307640 sulfone formation. Further, LY307640 competitively inhibited S-mephenytoin 4'-hydroxylation and midazolam 1'-hydroxylation as did the structurally related compound, omeprazole. For the inhibition of S-mephenytoin 4'-hydroxylation and midazolam 1'-hydroxylation, LY307640 had higher Ki(apparent) values than that of omeprazole. These studies demonstrate that the high affinity enzymes which catalyze the formation of the desmethyl and sulfone metabolites of LY307640 are, respectively, CYP 2C19 and CYP 3A. In addition, the inhibition data suggest that LY307640 has less potential to inhibit the metabolism of CYP 2C19 substrates compared to omeprazole, and that LY307640 and omeprazole have a similarly low potential to inhibit the metabolism of CYP 3A substrates. | ||||||||
| 191 | 44.35 | 11602509 | 2002.01.07 | + | + | Gemfibrozil is a potent inhibitor of human cytochrome P450 2C9. | Drug Metab Dispos | |
| X Wen, JS Wang, JT Backman, KT Kivistö, PJ Neuvonen, | ||||||||
| The in vitro inhibitory effects of gemfibrozil on cytochrome P450 (CYP) 1A2 (phenacetin O-deethylation), CYP2A6 (coumarin 7-hydroxylation), CYP2C9 (tolbutamide hydroxylation), CYP2C19 (S-mephenytoin 4'-hydroxylation), CYP2D6 (dextromethorphan O-deethylation), CYP2E1 (chlorzoxazone 6-hydroxylation), and CYP3A4 (midazolam 1'-hydroxylation) activities were examined using pooled human liver microsomes. The in vivo drug interactions of gemfibrozil were predicted in vitro using the [I]/([I] + K(i)) values. Gemfibrozil strongly and competitively inhibited CYP2C9 activity, with a K(i) (IC(50)) value of 5.8 (9.6) microM. In addition, gemfibrozil exhibited somewhat smaller inhibitory effects on CYP2C19 and CYP1A2 activities, with K(i) (IC(50)) values of 24 (47) microM and 82 (136) microM, respectively. With concentrations up to 250 microM, gemfibrozil showed no appreciable effect on CYP2A6, CYP2D6, CYP2E1, and CYP3A4 activities. Based on [I]/([I] + K(i)) values calculated using peak total (or unbound) plasma concentration of gemfibrozil, 96% (56%), 86% (24%), and 64% (8%) inhibition of the clearance of CYP2C9, CYP2C19, and CYP1A2 substrates could be expected, respectively. In conclusion, gemfibrozil inhibits the activity of CYP2C9 at clinically relevant concentrations, and this is the likely mechanism by which gemfibrozil interacts with CYP2C9 substrate drugs, such as warfarin and glyburide. Gemfibrozil may also impair clearance of CYP2C19 and CYP1A2 substrates, but inhibition of other CYP isoforms is unlikely. | ||||||||
| 192 | 44.35 | 14637391 | 2004.04.01 | + | + | Polymorphisms of estrogen synthesizing and metabolizing genes and breast cancer risk in Japanese women. | Biomed Pharmacother | |
| Y Miyoshi, S Noguchi, | ||||||||
| Recent success of chemoprevention with tamoxifen has opened a new era wherein prevention of breast cancer is much more emphasized than treatment of established breast cancer. Since tamoxifen has been shown to reduce the risk of estrogen receptor (ER)-positive, but not ER-negative, breast cancer in the chemoprevention trial (P-1), it seems to be important to develop risk factors for ER-positive breast cancer in order to select the candidates for chemoprevention more appropriately. Estrogens, the major risk factors for breast cancer, are speculated to affect breast cancer risk through ER, thus, genetic polymorphisms of the genes involved in the estrogens biosynthesis and metabolism are expected as risk factors for ER-positive breast cancer. Significance of polymorphisms of the genes involved in estrogens biosynthesis (CYP17, CYP19) and metabolism (CYP1A1, CYP1B1, COMT) in modulating the susceptibility to breast cancer is reviewed. The ethnic difference of the variant allele frequencies between Caucasian women and Asian women is also discussed. | ||||||||
| 193 | 44.34 | 10581492 | 2000.02.24 | + | + | Novel polymorphism in the promoter and coding regions of the human cholecystokinin B receptor gene: an association analysis with schizophrenia. | Am J Med Genet | |
| H Tachikawa, S Harada, Y Kawanishi, T Okubo, H Shiraishi, | ||||||||
| Genetic variations in the 5'-untranslated region and the coding region of the CCK-B receptor (CCK-BR) gene were investigated in healthy controls. Novel variants (-215 C-->A, Leu37Phe, Arg319Glu) were found in addition to the mutations (Val125Iso, His207His, Arg215His, 2491 C-->A) reported previously. In the present study, association analysis was carried out for these variants between 80 unrelated schizophrenic patients and 100 healthy controls. The genotype frequency of the -215 C-->A nucleotide substitution in the 5'-untranslated region of CCK-BR gene was significantly higher in the schizophrenic patients than in the controls (6.25%, P = 0.037). However, the difference was not significant after Bonferroni correction for multiple comparisons. Moreover, no association was found between the clinical characteristics of the patients and the genotype frequencies of the variants. These results suggest that the CCK-BR gene polymorphisms have no association with schizophrenia nor its clinical heterogeneity. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:700-704, 1999. | ||||||||
| 194 | 44.33 | 1688247 | 1993.06.10 | + | + | Identification of a novel CYP2D6 allele associated with poor metabolism of sparteine in a Japanese population. | Pharmacogenetics | |
| I Kondo, M Yonaha, K Okano, FJ Gonzalez, I Kanazawa, | ||||||||
| The relationship between genotypes associated with restriction fragment length polymorphisms at the P450 CYP2D locus and the metabolic phenotypes for sparteine in healthy Japanese subjects was investigated. Four distinct restriction fragments of 44 kb, 29 kb, 11.5 kb or 16 + 9 kb after digestion with Xba I were observed. The genotype of Xba I 11.5 kb, which is predictive of the poor metabolizer phenotype in Caucasians is also associated with Japanese poor metabolizers. Most Xba I 44 kb are associated with the extensive metabolizer phenotype. However, one Xba I 44 kb haplotype in linkage disequilibrium with a Bam HI restriction fragment length polymorphism allele, designated Bam HI 2.3 kb-, appears to be a novel mutant CYP2D6 allele in Japanese subjects having the poor metabolizer phenotype. | ||||||||
| 195 | 44.29 | 16086925 | 2005.12.02 | + | + | Candidate gene susceptibility variants predict intermediate end points but not angiographic coronary artery disease. | Am Heart J | |
| BM Whiting, JL Anderson, JB Muhlestein, BD Horne, TL Bair, RR Pearson, JF Carlquist, | ||||||||
| BACKGROUND: Moderate-sized studies have suggested that variants of candidate genes can influence laboratory markers of coronary artery disease (CAD), but whether they predict parallel changes in clinical CAD risk is unknown. METHODS: We studied a single nucleotide polymorphism (SNP) from each of the 5 candidate genes for intermediate (laboratory) and clinical (angiographic CAD) end points in a large cohort of patients. The 5 gene SNPs were cholesteryl ester transfer protein (CETP) TaqIB (N = 3219), ATP-binding cassette (ABCA1) G596A (N = 3302), lipoprotein lipase (LPL) HindIII (N = 909), plasminogen activator inhibitor, type 1 (PAI1), 4G/5G (N = 1142), and hepatic lipase (HL) C-541T (N = 4704). Intermediate outcomes were high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs). Cases had 1- to 3-vessel CAD (> or = 70% stenosis); controls had angiographically normal coronaries. RESULTS: Cholesteryl ester transfer protein predicted HDL (mean, B1B1 35.0 mg/dL, B2B2 38.6 mg/dL; P < .001) but not CAD (B1B1 74%, B2B2 70%; adjusted P = .35, odds ratio [OR] = 0.89). ABCA1 predicted HDL (mean, GG = 36.4 mg/dL, AA = 39.2 mg/dL; P = .02) but not CAD (GG 74%, AA 75%; adjusted P = .96, OR = 0.99). HL predicted HDL (CC 37.1 mg/dL, TT 40.9 mg/dL; P = .002) but not CAD (CC 71%, TT 68%, adjusted P = .66, OR = 0.94). LPL predicted TG (median: [++] 134, [--] 98 mg/dL; P < .001) but not CAD ([++] 79%, [--] 79%; adjusted P = .99, OR = 1.00). PAI1 predicted TG (median, 4G4G 130 mg/dL, 5G5G 148 mg/dL; P = .16), but not CAD (4G4G 77%, 5G5G 76%; adjusted P = .62, OR = 1.11). CONCLUSIONS: Five SNPs predicted differences in risk-related lipids but not angiographic CAD. These discrepancies suggest that genetic determinants of CAD are complex and intermediate phenotypes are poor surrogates. These findings have important implications for future directions in genetic research. | ||||||||
| 196 | 44.29 | 10448083 | 1999.09.23 | + | + | The significance of the homozygous CYP2A6 deletion on nicotine metabolism: a new genotyping method of CYP2A6 using a single PCR-RFLP. | Biochem Biophys Res Commun | |
| K Kitagawa, N Kunugita, T Katoh, M Yang, T Kawamoto, | ||||||||
| A convenient and specific CYP2A6 genotyping method was developed in this study. This method consisting of a single PCR-RFLP is capable of resolving the genotype into either CYP2A6*1 (wild type), CYP2A6*2, or CYP2A6*3. Among 252 Japanese persons genotyped, 241 were genotyped as the wild type, 1 as an unknown variant, and none as either CYP2A6*2 or CYP2A6*3. A homozygous deletion was found in the 10 remaining subjects. To clarify the metabolic significance of this deletion in the whole human body, urinary cotinine, the principal metabolite of nicotine, was analyzed subsequent to smoking. Cumulated urinary cotinine excretion in the homozygously CYP2A6-deleted individuals was about one-seventh compared to the control group (wild type). This study provides a firm experimental basis for correlating genotypic characterization of CYP2A6 with phenotypic expression of nicotine metabolism. | ||||||||
| 197 | 44.24 | 16489062 | 2006.04.17 | + | + | Genetic characterization of fas-associated phosphatase-1 as a putative tumor suppressor gene on chromosome 4q21.3 in hepatocellular carcinoma. | Clin Cancer Res | |
| SH Yeh, DC Wu, CY Tsai, TJ Kuo, WC Yu, YS Chang, CL Chen, CF Chang, DS Chen, PJ Chen, | ||||||||
| PURPOSE: Allelic loss at chromosome 4q21-23 occurs frequently in human hepatocellular carcinoma, and the putative tumor suppressor gene (TSG) has not yet been identified. We studied the Fas-associated phosphatase-1 (FAP-1) gene as a potential candidate TSG in this region. EXPERIMENTAL DESIGN: The expression level of FAP-1 RNA in hepatocellular carcinomas was evaluated by RNase protection and quantitative PCR. Sodium bisulfite modification and subsequent single-strand conformational polymorphism and sequence analyses were used to assay the methylation of CpGs at FAP-1 promoter. Direct sequencing of the FAP-1 coding region was conducted for detecting the genetic mutations. Two common single nucleotide polymorphisms of FAP-1 were selected for evaluating their association with the hepatocellular carcinoma trait in sporadic and familial hepatocellular carcinomas. Moreover, the functional effect of FAP-1 on cellular proliferation has been evaluated by small interfering RNA approach. RESULTS: Around 50% of hepatocellular carcinomas showed significantly decreased expression of FAP-1 compared with the corresponding nontumorous liver tissues. In most cases, the RNA level was well correlated with the methylation status of promoter CpGs, suggesting that the promoter methylation may contribute to the down-regulation. Several genetic mutations of FAP-1 have been identified in hepatocellular carcinomas. The G/G genotype of FAP-1 cSNP6304 was significantly associated with the increased risk of multiplex familial hepatocellular carcinomas (odds ratio, 2.44; 95% confidence interval, 1.19-5.01). Finally, knockdown expression of FAP-1 was shown to enhance the cellular proliferation in PLC5 cells. CONCLUSIONS: FAP-1 could be inactivated during hepatocarcinogenesis, mainly attributed by allelic loss and promoter methylation. The genetic mutations and polymorphisms may also confront with the higher hepatocellular carcinoma risk. These results first suggested FAP-1 as a putative TSG in hepatocarcinogenesis. | ||||||||
| 198 | 44.23 | 15970794 | 2005.10.13 | + | + | Common genetic polymorphisms in the 5'-flanking region of the SULT1A1 gene: haplotypes and their association with platelet enzymatic activity. | Pharmacogenet Genomics | |
| B Ning, S Nowell, C Sweeney, CB Ambrosone, S Williams, X Miao, G Liang, D Lin, A Stone, DL Ratnasinghe, M Manjanatha, NP Lang, FF Kadlubar, | ||||||||
| SULT1A1 is a phase II detoxification enzyme involved in the biotransformation of a wide variety of endogenous and exogenous phenolic compounds. Human platelet SULT1A1 enzymatic activity shows marked inter-individual variability and a common coding polymorphism, SULT1A1*1/*2, has been described that accounts for a proportion of this variability. We examined the 5'-flanking region of the SULT1A1 gene to determine if genetic variability in this portion of the gene influenced enzymatic activity. Direct sequencing revealed five common genetic polymorphisms (-624G>C, -396G>A, -358A>C, -341C>G and -294T>C) that were present at different allele frequencies in Caucasian, African-American and Chinese groups. Platelet SULT1A1 enzymatic activity was significantly correlated with individual promoter region polymorphisms and the associations were different between African-Americans and Caucasians. Haplotypes were constructed and platelet enzymatic activity according to haplotype was examined. The haplotypes were also significantly correlated with activity; haplotypes GAACT and GGACT (accounting for 13% and 5% of inter-individual variability in platelet activity, respectively) were important in Caucasians while haplotypes GAACC, GAACT and GGACC (accounting for 8%, 5% and 4% of variability) were significantly associated with activity in African-Americans. The coding region polymorphism, SULT1A1*1/*2 was in linkage disequilibrium with the promoter region polymorphisms and showed no effect on activity when examined in the context of the 5'-flanking region polymorphisms. These studies indicate that variation in the promoter region of the SULT1A1 gene exerts a significant influence on enzymatic activity. | ||||||||
| 199 | 44.21 | 8528268 | 1996.01.31 | + | + | Detection of the poor metabolizer-associated CYP2D6(D) gene deletion allele by long-PCR technology. | Pharmacogenetics | |
| VM Steen, OA Andreassen, AK Daly, T Tefre, AL Børresen, JR Idle, AK Gulbrandsen, | ||||||||
| The cytochrome P450 enzyme debrisoquine 4-hydroxylase metabolizes many different classes of commonly used drugs, such as antidepressants and neuroleptics. Deficient hydroxylation of debrisoquine, known as the poor metabolizer (PM) phenotype, affects 5-10% of Caucasians and may lead to adverse reactions upon administration of drugs in standard doses. This autosomal recessive metabolic deficiency is caused by the possession of two PM-associated mutations in the human CYP2D6 gene locus coding for the enzyme. These mutations include at least four different single base mutations and two different large gene deletion alleles. The single base mutations can be rapidly detected by PCR methods. In contrast, the large gene deletions have so far only been directly identified by RFLP analysis. By the use of sequence data previously published by others, we report here an alignment of different CYP2D alleles to focus on the presence of almost completely identical sequences immediately downstream of both CYP2D7 and CYP2D6 which may seriously complicate and interfere with PCR-based detection of the gene deletion. Based on this analysis, we have developed a rapid assay which, for the first time, detects the 13kb (also called 11.5 kb) Xba I gene deletion allele by the use of long-PCR technology. The primers were designed to amplify a 3.5 kb PCR product in the presence of this D6(D) allele. We have evaluated the method on 23 different DNA samples heterozygous (n = 22) or homozygous (n = 1) for the 13 kb gene deletion allele (previously typed by RFLP analyses). All samples were correctly identified by the assay. The PCR method did not detect the rare 11 kb Xba I gene deletion allele (n = 5), and there was no false positive amplification from deletion negative DNA samples (n = 47). This sensitive and specific PCR-based assay for detection of the D6(D) allele will improve the scientific and clinical use of CYP2D6 genotyping. | ||||||||
| 200 | 44.20 | 15448003 | 2005.01.11 | + | + | Characterization of mutator phenotype in familial colorectal cancer patients not fulfilling amsterdam criteria. | Clin Cancer Res | |
| JC Kim, KH Lee, IH Ka, KH Koo, SA Roh, HC Kim, CS Yu, TW Kim, HM Chang, GY Gong, JS Kim, | ||||||||
| PURPOSE: Although the mutator phenotype, including genetic and epigenetic alterations of the mismatch repair (MMR) system, seems to be pronounced in familial colorectal cancer, there have been few integrative studies comprising the entire mutator pathway. This study was done to identify the entire mutator pathway determining risk factors in patients with familial colorectal cancer not fulfilling the Amsterdam criteria. EXPERIMENTAL DESIGN: We consecutively recruited 134 colorectal cancer patients with a family history of accompanying cancers. Patients with hereditary nonpolyposis colorectal cancer meeting the Amsterdam criteria, familial adenomatous polyposis, or those receiving preoperative radiotherapy were excluded. Mutator phenotype was assessed by assaying microsatellite instability (MSI) at 24 markers, hMLH1-promoter methylation, mutations at MMR genes (hMLH1, hMSH2, hMSH6, and hPMS2), and immune staining of MMR proteins (hMLH1, hMSH2, hMSH6, hPMS1, and hPMS2). RESULTS: Of the 208 cancers in first-degree and/or second-degree relatives of patients, colorectal and gastric cancers (81%) were most common. Of the 134 proband colorectal cancers, 23 (17%) were MSI in high level, and 32 (24%) were MSI in low level. MMR alterations, including known polymorphism and splicing substitution, were identified in eight patients (6%). Twenty-eight tumors with mutator phenotype were further identified by hMLH1-promoter methylation and/or loss of MMR protein expression. In 51 tumors (38%), mutator phenotype was associated with right-sided colon cancer (P < 0.001) and younger age at onset (P=0.032), but the number of patients with a mutator phenotype did not differ with respect to inheritance patterns of accompanying cancers, either successive or horizontal transmission (P=0.815). Familial impact value, which differentially associated the degree of relatives with all accompanying cancers, effectively discriminated MSI in high level from microsatellite stable/MSI in low level tumors. CONCLUSION: Familial colorectal cancer may be associated with multiple occurrences of colorectal or accompanying cancers inherited by dominant or recessive transmission. MMR gene mutations, however, are less associated with mutator phenotype in familial colorectal cancer. | ||||||||
| 201 | 44.20 | 10889530 | 2000.09.12 | + | + | Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1). | Mol Psychiatry | |
| F Grünhage, TG Schulze, DJ Müller, M Lanczik, E Franzek, M Albus, M Borrmann-Hassenbach, M Knapp, S Cichon, W Maier, M Rietschel, P Propping, MM Nöthen, | ||||||||
| The dopamine transporter (DAT) plays a central role in dopaminergic neurotransmission in the human brain. Genetic association studies have used a variable number of tandem repeat (VNTR) polymorphism in the 3'-flanking region of the dopamine transporter gene (DAT1) to implicate the DAT in the development of various neuropsychiatric disorders. In this study, we have examined the possibility that a mutation exists in the coding region of the DAT1 gene which through linkage disequilibrium accounts for the observed associations. The complete coding region, as well as exon-intron boundaries, was screened in 91 unrelated individuals including 45 patients with bipolar affective disorder and 46 healthy control individuals by the means of single strand conformation analysis. Our findings suggest that the DAT1 gene is highly conserved since we detected only two rare missense substitutions (Ala559Val, Glu602Gly) and three silent mutations (242C/T, 1342A/G, and 1859C/T) in the whole coding region. Five sequence variants were observed in intronic sequences but none affects known splice sites. The lack of frequent variants of possible functional relevance indicates that genetic variation in the coding region of the DAT1 gene is not responsible for the previously observed associations with neuropsychiatric disorders. The two rare missense substitutions were found in single bipolar patients but not in controls. Investigation of the patients' families revealed independent segregation between the Ala559Val variant and affective disorder. The Glu602Gly variant was inherited by the proband from an affected father. It therefore remains possible that Glu602Gly may be a rare cause of bipolar affective disorder. | ||||||||
| 202 | 44.19 | 16768547 | 2007.02.12 | + | + | The BARD1 Cys557Ser variant and breast cancer risk in Iceland. | PLoS Med | |
| SN Stacey, P Sulem, OT Johannsson, A Helgason, J Gudmundsson, JP Kostic, K Kristjansson, T Jonsdottir, H Sigurdsson, J Hrafnkelsson, J Johannsson, T Sveinsson, G Myrdal, HN Grimsson, JT Bergthorsson, LT Amundadottir, JR Gulcher, U Thorsteinsdottir, A Kong, K Stefansson, | ||||||||
| BACKGROUND: Most, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer. METHODS AND FINDINGS: The Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.11-3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22-4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16-8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents. CONCLUSIONS: Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation. | ||||||||
| 203 | 44.12 | 15380858 | 2004.12.30 | + | + | Association study of dopamine transporter gene and schizophrenia in Korean population using multiple single nucleotide polymorphism markers. | Prog Neuropsychopharmacol Biol Psychiatry | |
| SH Jeong, EJ Joo, YM Ahn, YS Kim, | ||||||||
| Inherited or acquired dysfunction of the dopamine system is believed to underlie the core symptoms of schizophrenia, and there are some evidences that dopamine transporter activity may be altered in schizophrenic patients. Therefore, dopamine transporter gene (DAT1) has been traditionally considered a probable candidate gene for the association study of schizophrenia. Until now, association studies of the dopamine transporter gene (DAT1) with schizophrenia have yielded largely negative results. However, these results cannot be regarded as conclusive in that they were all obtained from just a single marker, that is, 3' untranslated region variable number of tandem repeat (VNTR). We have therefore tried to find other single nucleotide polymorphisms (SNPs) in DAT1 gene and to use them as additional markers for the association study of schizophrenia. Searching for the SNPs had been done with 50 Korean schizophrenic patients. DNA sequences encompassing the whole exon and flanking exon-intron junctions were amplified and searched for the presence of SNPs. Total of five SNPs were found. Among these, three SNPs (1215A>G, 1398C>T, IVS11+14G>A) as well as the 3' untranslated region VNTR were selected as the markers to be genotyped. The allelic and genotypic frequencies of these markers were determined in 252 schizophrenic patients and 271 controls and compared between them. The frequencies of algorithmically derived haplotypes were also compared. No evidence of association was found between any of these markers and schizophrenia. The result using haplotypes was also negative. However, when the patient subgroup with verified familial history and the subgroup with early age of onset were re-analyzed, weak trend of association between 1398C>T SNP marker with schizophrenia was found in both cases. In accordance with the previous literature, we could not find any evidence of association between DAT1 gene and schizophrenia. This result acquired more certainty because not only the VNTR but several SNPs present in DAT1 gene and newly constructed haplotypes were also used as additional markers. However, the finding of weak association between one of the SNP markers (1398C>T) and the specific subgroups of schizophrenia patients added further support to the importance of defining more homogenous subgroups in association studies. | ||||||||
| 204 | 44.12 | 9797796 | 1998.11.10 | + | + | Bantu Tanzanians have a decreased capacity to metabolize omeprazole and mephenytoin in relation to their CYP2C19 genotype. | Clin Pharmacol Ther | |
| K Herrlin, AY Massele, M Jande, C Alm, G Tybring, YA Abdi, A Wennerholm, I Johansson, ML Dahl, L Bertilsson, LL Gustafsson, | ||||||||
| OBJECTIVE: To investigate the CYP2C19 polymorphism in Tanzanians because this enzyme shows large interindividual differences in activity and metabolizes several drugs of importance in Africa, especially the antimalarial agent chloroguanide (INN, proguanil). METHODS: Two hundred fifty-one Tanzanian healthy volunteers were phenotyped with respect to CYP2C19 with use of a single oral dose of mephenytoin (n = 106), a single oral dose of omeprazole (n = 207), or both. Sixty-two were phenotyped with both probe drugs. The urinary 0- to 8-hour S/R-mephenytoin ratio and the plasma omeprazole metabolic ratio (MR) (omeprazole/hydroxyomeprazole) 3 hours after drug intake were determined. The genotype was determined by analysis for CYP2C19*1 (wt), CYP2C19*2 (m1), and CYP2C19*3 (m2). Ten subjects with high omeprazole MR were screened for new mutations in the CYP2C19 gene by searching for single-strand conformation polymorphisms (SSCP). RESULTS: Eight subjects were classified as mephenytoin poor metabolizers (7.5%). Only 5 of these were homozygous for mutated alleles. The S/R ratio was skewed to the right (lower CYP2C19 activity) compared with other ethnic groups studied previously. No new mutations were found with polymerase chain reaction (PCR)-SSCP. We found 30 volunteers (14.5%) with an MR > 7, which is the antimode found previously in white subjects and Asian subjects. Of the 251 volunteers genotyped, 3.2% were homozygous for mutated alleles and 66.1% were homozygous for the wild-type allele. The allele frequencies of CYP2C19*1, *2, and *3 were 81.5%, 17.9%, and 0.6%, respectively. The correlation between the S/R-mephenytoin ratio and the omeprazole MR was significant (Spearman r = 0.59; P < .01). CONCLUSION: Tanzanians have a decreased capacity to metabolize both omeprazole and mephenytoin when their genotype is compared with metabolic capacity and genotype in other previously studied populations. We identified a low frequency of the Asian allele (CYP2C19*3). Although we did not find any new mutations, our results may be consistent with the presence of yet-unidentified mutations of CYP2C19 that causes decreased CYP2C19 activity in the Tanzanian population. | ||||||||
| 205 | 44.10 | 14583682 | 2004.07.14 | + | + | Decreased coumarin 7-hydroxylase activities and CYP2A6 expression levels in humans caused by genetic polymorphism in CYP2A6 promoter region (CYP2A6*9). | Pharmacogenetics | |
| K Kiyotani, H Yamazaki, M Fujieda, S Iwano, K Matsumura, S Satarug, P Ujjin, T Shimada, FP Guengerich, A Parkinson, G Honda, K Nakagawa, T Ishizaki, T Kamataki, | ||||||||
| One of seven poor metabolizers of coumarin found in Thai subjects was previously genotyped as heterozygote for the CYP2A6*4 (whole deletion) and CYP2A6*9. Thus, we aimed to investigate the relationship between the genetic polymorphism in the TATA box of the CYP2A6 gene (CYP2A6*9), expression levels of CYP2A6 mRNA and coumarin 7-hydroxylase activities in human livers. Levels of CYP2A6 mRNA were quantified by real-time quantitative reverse transcriptase-polymerase chain reaction. The mean expression levels of CYP2A6 mRNA in individuals with CYP2A6*1/*4, CYP2A6*1/*9 and CYP2A6*4/*9 were 58%, 71% and 21% of the individuals genotyped as CYP2A6*1/*1, respectively. The mean in-vitro coumarin 7-hydroxylase activities in subjects carrying CYP2A6*1/*4, CYP2A6*1/*9 and CYP2A6*4/*9 were 41%, 71% and 12%, respectively, compared to those of the subjects judged as wild-type. Vmax values for coumarin 7-hydroxylation in the liver microsomes from human subjects with genotypes of CYP2A6*1/*1, CYP2A6*1/*4, CYP2A6*1/*9 and CYP2A6*4/*9 were 0.58, 0.26, 0.44 and 0.13 nmol/min/nmol total P450, respectively. CYP2A6 protein levels in human liver microsomes with the CYP2A6*4 and the CYP2A6*9 alleles were markedly decreased. These results suggest that the genetic polymorphism in the promoter region of the CYP2A6 gene (CYP2A6*9) reduced the expression levels of CYP2A6 mRNA and protein in human livers, resulting in the decrease of coumarin 7-hydroxylase activities. Individuals judged as CYP2A6*4/*9 were expected to be poor metabolizers, having extremely low activity of CYP2A6. | ||||||||
| 206 | 44.06 | 9109440 | 1997.05.09 | + | + | Intestinal transcription and synthesis of apolipoprotein AI is regulated by five natural polymorphisms upstream of the apolipoprotein CIII gene. | J Clin Invest | |
| S Naganawa, HN Ginsberg, RM Glickman, GS Ginsburg, | ||||||||
| To understand the factors contributing to the synthesis of human apolipoprotein AI (apoAI), relative apoAI synthesis was measured from endoscopic biopsy samples obtained from 18 healthy volunteers. The relative amount of apoAI synthesis was directly correlated with steady state intestinal apoAI mRNA levels and a 10-fold within-group variability was observed. Analysis of genomic DNA from the subjects revealed five polymorphic sites which defined two haplotypes in the intestinal enhancer region of the apoAI gene located upstream of the apolipoprotein CIII gene transcriptional start site (+ 1): (-641 C to A, -630 G to A, -625 T to deletion, -482 C to T, and -455 T to C). The population frequencies of the wild-type and mutant alleles were 0.53 and 0.44, respectively. Mean steady state apoAI mRNA levels and mean relative apoAI synthesis were 49 and 37% lower, respectively, in homozygotes for the mutant allele and 28 and 41% lower, respectively, in heterozygotes than in homozygotes for the wild-type allele (P < 0.05 for both). Site-directed mutants of apoAI gene promoter/reporter constructs containing the above mutations were transfected into Caco-2 cells and showed a 46% decrease in transcriptional activity compared with the wild type (P < 0.001); however, no significant differences were observed in HepG2 cells. Electrophoretic mobility shift assays showed that the mutated sequences from -655 to -610 bound Caco-2 cell nuclear protein(s) while the wild type did not. These results indicate that intestinal apoAI gene transcription and protein synthesis are genetically determined and are reduced in the presence of common mutations which induced binding of nuclear protein(s), possibly a transcriptional repressor. | ||||||||
| 207 | 44.06 | 11443533 | 2001.09.06 | + | + | Exon/intron boundaries, novel polymorphisms, and association analysis with schizophrenia of the human synaptic vesicle monoamine transporter (SVMT) gene. | Mol Psychiatry | |
| H Kunugi, S Ishida, A Akahane, S Nanko, | ||||||||
| The synaptic vesicular monoamine transporter (SVMT), alternatively vesicular monoamine transporter 2 (VMAT2), pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles. Altered functions of SVMT have been implicated in the pathogensis of several neuropsychiatric diseases. We determined exon/intron boundaries of the human SVMT gene and performed mutational analysis for the exonic and neighboring intronic regions of the gene. Detected polymorphisms were subject to association analysis with schizophrenia in a family-based design. The human SVMT gene consists, of 16 exons and 15 introns, which is consistent with the murine SVMT gene. When mutational analysis was performed by the single strand conformational polymorphism (SSCP) analysis, we found two and four single nucleotide polymorphisms (SNPs) in exons and neighboring introns, respectively. Neither exonic SNP results in an amino acid change. In family-based association analyses in a sample of 50 Japanese schizophrenics and their parents, no significant association was found for the intronic polymorphisms. Our data suggest that there is no common polymorphism in the SVMT gene affecting the primary structure of the human SVMT protein. Furthermore, we obtained no evidence for the major effect of the novel polymorphisms on susceptibility to schizophrenia. | ||||||||
| 208 | 44.02 | 11803454 | 2002.04.19 | + | + | A family-based and case-control association study of the NOTCH4 gene and schizophrenia. | Mol Psychiatry | |
| JB Fan, JX Tang, NF Gu, GY Feng, FG Zou, YL Xing, JG Shi, SM Zhao, SM Zhu, LP Ji, WW Sun, YL Zheng, WQ Liu, G Breen, D St Clair, L He, | ||||||||
| Recently a strong positive association between schizophrenia and Notch4 has been reported. Both individual markers and haplotypes showed association with the disease, with five markers (three microsatellites and two SNPs) being tested. In order to test this finding we genotyped these markers in the Han Chinese population using a sample of 544 cases and 621 controls as well as >300 trios. Analysis of allele, genotype and haplotype frequencies in both samples showed no association between the markers and the disease. Our results would indicate that a significant role for the Notch4 gene in schizophrenia can be ruled out in the Han Chinese. However, similar studies are necessary in the Caucasian population as linkage disequilibrium arrangements and founder effects may differ between these two populations. | ||||||||
| 209 | 43.99 | 15638952 | 2005.06.13 | + | + | Family-based association study of the 5-HT transporter gene and schizophrenia. | Int J Neuropsychopharmacol | |
| C Dubertret, N Hanoun, J Adès, M Hamon, P Gorwood, | ||||||||
| The gene coding for the 5-HT transporter (5-HTT) is considered as a candidate gene for schizophrenia, because this transporter plays a key role in serotonin neurotransmission. Previous genetic studies focusing on this gene yielded conflicting results, presumably because of stratification biases linked to the case-control association study approach, and the potential genetic and phenotypic heterogeneity of schizophrenia. We investigated the 5-HTTLPR and 17-bp VNTR (variable number of tandem repeats) polymorphisms of this gene in 103 trios using the transmission disequilibrium test. No preferential transmission of either allele of the 17-bp VNTR was observed, but an excess of transmission of the L allele of the 5-HTTLPR polymorphism was detected (p = 0.03). As the haplotype analyses did not improve the strength of the association, our data provide convergent evidence for a significant role of the 5-HTTLPR promoter polymorphism of the 5-HTT gene in the vulnerability to schizophrenia. | ||||||||
| 210 | 43.98 | 17617792 | 2007.11.08 | + | + | The low frequency of defective TPMT alleles in Turkish population: a study on pediatric patients with acute lymphoblastic leukemia. | Am J Hematol | |
| TB Tumer, G Ulusoy, O Adali, G Sahin, S Gozdasoglu, E Arinç, | ||||||||
| 6-Mercaptopurine (6MP) is an essential anticancer drug used in the treatment of childhood acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (TPMT) polymorphisms are the major determinants of interindividual differences in the severe toxicity or efficacy of 6MP. Four variant alleles, TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3C, are responsible over the 80% of low or undetectable enzyme activity. The frequencies of these variants were investigated among 106 children with ALL in Turkish population. TPMT*3A and TPMT*3C were the only deficiency alleles detected in Turkish population with an allele frequency of 0.9% for both. While *3C allele frequency in Turkish population was found to be very similar to Asian and other Caucasian populations, *3A allele frequency was significantly (P < 0.05) lower. So far, studies showed that the genetic polymorphisms of other drug metabolizing enzymes like CYP2E1, CYP1A1, GSTM1/ T1 in Turkish population were similar to Caucasian populations. However, we found that the distribution of TPMT polymorphisms in Turkish population was significantly lower than those in other Caucasians like British, French, and Italian whereas the distributions of TPMT variants were found to be very similar to Kazak population which is also Caucasian in ethnic origin. In this study, the clinical histories of the patients in the sample population were also examined, retrospectively. The patients with heterozygous or homozygous mutant genotypes had developed severe neutropenia and infection during 6MP therapy. The study provides the first data on the frequency of common TPMT variants in the Turkish population, based on analysis of pediatric patients with ALL. | ||||||||
| 211 | 43.98 | 10739176 | 2000.05.17 | + | Polymorphism of the cytochrome P450 (CYP) 2C9 gene in Japanese epileptic patients: genetic analysis of the CYP2C9 locus. | Pharmacogenetics | ||
| J Imai, I Ieiri, K Mamiya, S Miyahara, H Furuumi, E Nanba, M Yamane, Y Fukumaki, H Ninomiya, N Tashiro, K Otsubo, S Higuchi, | ||||||||
| 212 | 43.92 | 11139588 | 2001.05.10 | + | + | Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. | J Biol Chem | |
| RA Campbell, P Bhat-Nakshatri, NM Patel, D Constantinidou, S Ali, H Nakshatri, | ||||||||
| Estrogen receptors (ERs) mediate most of the biological effects of estrogen in mammary and uterine epithelial cells by binding to estrogen response elements in the promoter region of target genes or through protein-protein interactions. Anti-estrogens such as tamoxifen inhibit the growth of ER-positive breast cancers by reducing the expression of estrogen-regulated genes. However, anti-estrogen-resistant growth of ER-positive tumors remains a significant clinical problem. Here we show that phosphatidylinositol (PI) 3-kinase and AKT activate ERalpha in the absence of estrogen. Although PI 3-kinase increased the activity of both estrogen-independent activation function 1 (AF-1) and estrogen-dependent activation function 2 (AF-2) of ERalpha, AKT increased the activity of only AF-1. PTEN and a catalytically inactive AKT decreased PI 3-kinase-induced AF-1 activity, suggesting that PI 3-kinase utilizes AKT-dependent and AKT-independent pathways in activating ERalpha. The consensus AKT phosphorylation site Ser-167 of ERalpha is required for phosphorylation and activation by AKT. In addition, LY294002, a specific inhibitor of the PI 3-kinase/AKT pathway, reduced phosphorylation of ERalpha in vivo. Moreover, AKT overexpression led to up-regulation of estrogen-regulated pS2 gene, Bcl-2, and macrophage inhibitory cytokine 1. We demonstrate that AKT protects breast cancer cells from tamoxifen-induced apoptosis. Taken together, these results define a molecular link between activation of the PI 3-kinase/AKT survival pathways, hormone-independent activation of ERalpha, and inhibition of tamoxifen-induced apoptotic regression. | ||||||||
| 213 | 43.90 | 16421598 | 2006.04.27 | + | + | A CXCL2 tandem repeat promoter polymorphism is associated with susceptibility to severe sepsis in the Spanish population. | Genes Immun | |
| C Flores, N Maca-Meyer, L Pérez-Méndez, R Sangüesa, E Espinosa, A Muriel, J Blanco, J Villar, | ||||||||
| Sepsis describes a complex clinical syndrome resulting from a systemic inflammatory response to bacteria. Functional studies in animal models of sepsis have catalogued CXCL2 as a candidate gene for the development of the disease. We hypothesized that CXCL2 polymorphisms may confer susceptibility to sepsis and performed an association study using 178 severe sepsis patients and 357 population-based controls. We selected two polymorphisms from the promoter of the gene (-437A/G and -665(AC)n), and analyzed whether haplotypes or single loci were associated with disease susceptibility. An overall test of differentiation showed that haplotype distribution was not different between cases and controls (P=0.407). Likewise, -437A/G was not associated with disease susceptibility (heterozygote odds ratio (OR) 0.68 (0.47-1.03), and homozygote OR 0.86 (0.56-1.32); P=0.706). However, for the -665(AC)n, we found that the 24+/-1 repeat alleles were associated with susceptibility (heterozygote OR 2.82 (1.10-7.24), and homozygote OR 3.65 (1.41-9.43); P=0.0006). This association remained significant when using a multiple logistic regression analysis (OR 2.23; 95% confidence intervals (95% CI) 1.22-4.03; P=0.008) and after a genomic control adjustment (P=0.017). Although replicate studies and functional assays are needed, these results suggest that CXCL2 gene variants may contribute to the development of severe sepsis. | ||||||||
| 214 | 43.88 | 15908806 | 2006.04.25 | + | + | Effect of ABCG2 genotype on the oral bioavailability of topotecan. | Cancer Biol Ther | |
| A Sparreboom, WJ Loos, H Burger, TM Sissung, J Verweij, WD Figg, K Nooter, H Gelderblom, | ||||||||
| ABCG2 (BCRP/MXR/ABCP) functions as an efflux transporter for many agents, including topotecan, and the protein is expressed at high levels in the human intestine. Some individuals possess a nonsynonymous variant in the ABCG2 gene at nucleotide 421, substituting lysine for glutamine on position 141 at exon 5. The present pilot study indicates that this genotype results in a 30% reduced efflux transport of topotecan in vitro compared to the wild-type. In a preliminary fashion, the heterozygous CA allele observed in two patients was associated with a 1.34-fold increased oral bioavailability of topotecan compared to the bioavailability in ten patients with the wild-type allele (42.0% versus 31.4%; p = 0.037). It is suggested that the high frequency of the A allele in certain ethnic groups may have therapeutic implications for individuals treated with topotecan or other ABCG2 substrates. | ||||||||
| 215 | 43.84 | 11408789 | 2001.08.30 | + | + | Association study for a functional serotonin transporter gene polymorphism and late-onset Alzheimer's disease for Chinese patients. | Neuropsychobiology | |
| SJ Tsai, CJ Hong, TY Liu, CY Cheng, HC Liu, | ||||||||
| Two recent studies have demonstrated an association for a deletion/insertion polymorphism within the promoter region of the serotonin transporter gene (5-HTTLPR), and Alzheimer's disease (AD). According to these studies, subjects with the short variant of the 5-HTTLPR gene are at increased risk for AD; however, this finding has not been confirmed by other workers. To evaluate the role of the 5-HTTLPR gene in susceptibility for AD, we conducted an association study for this polymorphism in a Chinese population. No significant differences were determined for genotype distribution or allele frequencies, comparing AD patients and normal controls. Even dividing the population into subgroups according to the presence of the APOE epsilon4 allele, no differences for genotype or allele frequencies were determined, comparing patients and controls. These results suggest that it is unlikely that the 5-HTTLPR polymorphism plays a substantial role in conferring susceptibility to AD. | ||||||||
| 216 | 43.83 | 7648765 | 1995.09.25 | + | + | Comparison of the interaction potential of a new proton pump inhibitor, E3810, versus omeprazole with diazepam in extensive and poor metabolizers of S-mephenytoin 4'-hydroxylation. | Clin Pharmacol Ther | |
| T Ishizaki, K Chiba, K Manabe, E Koyama, M Hayashi, S Yasuda, Y Horai, Y Tomono, C Yamato, T Toyoki, | ||||||||
| OBJECTIVE: To compare the interaction potential of E3810, [(+/-)-sodium 2-[[4-(3-methoxpropoxy)-3-methylpyridin-2-yl]methylsulfinyl] -1H-benzimidazole] a new proton pump inhibitor, and omeprazole with diazepam in relation to S-mephenytoin 4'-hydroxylation status. STUDY DESIGN: Fifteen healthy male volunteers consisting of six poor metabolizers and nine extensive metabolizers of S-mephenytoin 4'-hydroxylation participated in the study, where two poor and three extensive metabolizers each as a group were randomly allocated to one of the three different treatment sequences with a 3-week washout period among the three trial phases. Each volunteer received an oral once-daily dose of E3810 (20 mg), omeprazole (20 mg), or placebo for 23 days and an intravenous dose (0.1 mg/kg) of diazepam on posttreatment day 8. Plasma concentrations of diazepam and demethyldiazepam were measured up to 16 days after the administration of diazepam. RESULTS: Diazepam was more slowly metabolized in the poor metabolizers than in the extensive metabolizers. No significant effects of E3810 and omeprazole on any kinetic parameters of diazepam were observed in the poor metabolizers. In the extensive metabolizers, omeprazole significantly decreased the mean clearance of diazepam and increased its half-life, area under the plasma concentration-time curve, and mean residence time compared with E3810 and placebo (p < 0.05 or 0.01), whereas no changes in these kinetic parameters were observed during the treatment with E3810. Omeprazole significantly increased the mean area under the plasma concentration-time curve (0-16 days) of demethyldiazepam in the extensive metabolizers compared with placebo (p < 0.01), whereas E3810 significantly increased it in the poor metabolizers compared with omeprazole or placebo (p < 0.05). CONCLUSION: The results indicate that E3810 as a substrate goes less toward S-mephenytoin 4'-hydroxylase (CYP2C19) and has a much weaker, if any, potential to interact with diazepam compared with omeprazole. | ||||||||
| 217 | 43.78 | 16322495 | 2006.02.21 | + | + | Genotype and haplotype association study of the STRK1 region on 5q12 among Japanese: a case-control study. | Stroke | |
| T Nakayama, S Asai, N Sato, M Soma, | ||||||||
| BACKGROUND AND PURPOSE: Cerebral infarction is thought to be a multifactorial disease that is affected by several environmental factors and genetic variants. Gretarsdottir et al identified a candidate locus (STRK1) for cerebral infarction with a significant logarithm of odds score at 5q12 in whites in 2002 and subsequently identified the PDE4D gene as a susceptibility gene at this locus in 2003. The aims of this haplotype-based case-control study were to confirm, using microsatellite markers and single-nucleotide polymorphisms (SNPs), whether PDE4D is also a susceptibility gene for cerebral infarction in Japanese subjects. METHODS: Cerebral infarction was defined as noncardiogenic ischemic stroke with signs and symptoms lasting >1 month in duration. We genotyped 208 Japanese cerebral infarction patients and 270 non-cerebral infarction controls for 31 SNPs, 3 dinucleotide microsatellites, and 1 tetranucleotide variable number of tandem repeat. Haplotypes were constructed and their frequencies compared between the cerebral infarction patients and the controls. RESULTS: The haplotype-based case-control study revealed that in addition to the region of the PDE4D gene (P=0.002), another region (P<0.001) also existed within the STRK1 locus. CONCLUSIONS: The region of the PDE4D gene and the other newly detected region within the STRK1 locus were associated with cerebral infarction. | ||||||||
| 218 | 43.76 | 16094537 | 2006.08.31 | + | + | CYP2C9*3 allelic variant is associated with metabolism of irbesartan in Chinese population. | Eur J Clin Pharmacol | |
| X Hong, S Zhang, G Mao, S Jiang, Y Zhang, Y Yu, G Tang, H Xing, X Xu, | ||||||||
| OBJECTIVE: There is considerable variability in the individual pharmaceutical dosages required to achieve optimal therapeutic effects, which may be due to environmental or genetic factors. The objective of this study was to test the presence of the CYP2C9*3 allelic variant in the Chinese population and to investigate the association of this variant with both metabolism and therapeutic efficacy of irbesartan on essential hypertension. METHODS: In this study, we enrolled 711 subjects from Taihu County and 376 subjects from Dongzhi County in Anhui Province, China. Al | ||||||||