Dataset Information

Genetic variation of VKORC1 and CYP4F2 genes related to warfarin maintenance dose in patients with myocardial infarction.

ABSTRACT: The aim of this study was to investigate whether the VKORC1*3 (rs7294/9041 G?>?A), VKORC1*4 (rs17708472/6009 C?>?T), and CYP4F2 (rs2108622/1347 C?>?T) polymorphisms were associated with elevated warfarin maintenance dose requirements in patients with myocardial infarction (n = 105) from the Warfarin Aspirin Reinfarction Study (WARIS-II). We found significant associations between elevated warfarin dose requirements and VKORC1*3 and VKORC1*4 polymorphisms (P = .001 and P = .004, resp.), whereas CYP4F2 (1347 C?>?T) showed a weak association on higher warfarin dose requirements (P = .09). However, analysing these variant alleles in a regression analysis together with our previously reported data on VKORC1*2, CYP2C9*2 and CYP2C9*3 polymorphisms, gave no significant associations for neither VKORC1*3, VKORC1*4 nor CYP4F2 (1347 C?>?T). In conclusion, in patients with myocardial infarction, the individual contribution to warfarin dose requirements from VKORC1*3, VKORC1*4, and CYP4F2 (1347 C?>?T) polymorphisms was negligible. Our results indicate that pharmacogenetic testing for VKORC1*2, CYP2C9*2 and CYP2C9*3 is more informative regarding warfarin dose requirements than testing for VKORC1*3, VKORC1*4, and CYP4F2 (1347 C?>?T) polymorphisms.

SUBMITTER: Kringen MK

PROVIDER: S-EPMC2992873 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Genetic variation of VKORC1 and CYP4F2 genes related to warfarin maintenance dose in patients with myocardial infarction.

Kringen Marianne K MK Haug Kari Bente Foss KB Grimholt Runa M RM Stormo Camilla C Narum Sigrid S Opdal Mimi S MS Fosen Jan Toralf JT Piehler Armin P AP Johansen Per W PW Seljeflot Ingebjørg I Berg Jens Petter JP Brørs Odd O

Journal of biomedicine & biotechnology 20101124

The aim of this study was to investigate whether the VKORC1*3 (rs7294/9041 G > A), VKORC1*4 (rs17708472/6009 C > T), and CYP4F2 (rs2108622/1347 C > T) polymorphisms were associated with elevated warfarin maintenance dose requirements in patients with myocardial infarction (n = 105) from the Warfarin Aspirin Reinfarction Study (WARIS-II). We found significant associations between elevated warfarin dose requirements and VKORC1*3 and VKORC1*4 polymorphisms (P = .001 and P = .004, resp.), whereas CY ...[more]

PMID: 21127708

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Project description:We report the first genome-wide association study (GWAS) whose sample size (1,053 Swedish subjects) is sufficiently powered to detect genome-wide significance (p<1.5 x 10(-7)) for polymorphisms that modestly alter therapeutic warfarin dose. The anticoagulant drug warfarin is widely prescribed for reducing the risk of stroke, thrombosis, pulmonary embolism, and coronary malfunction. However, Caucasians vary widely (20-fold) in the dose needed for therapeutic anticoagulation, and hence prescribed doses may be too low (risking serious illness) or too high (risking severe bleeding). Prior work established that approximately 30% of the dose variance is explained by single nucleotide polymorphisms (SNPs) in the warfarin drug target VKORC1 and another approximately 12% by two non-synonymous SNPs (*2, *3) in the cytochrome P450 warfarin-metabolizing gene CYP2C9. We initially tested each of 325,997 GWAS SNPs for association with warfarin dose by univariate regression and found the strongest statistical signals (p<10(-78)) at SNPs clustering near VKORC1 and the second lowest p-values (p<10(-31)) emanating from CYP2C9. No other SNPs approached genome-wide significance. To enhance detection of weaker effects, we conducted multiple regression adjusting for known influences on warfarin dose (VKORC1, CYP2C9, age, gender) and identified a single SNP (rs2108622) with genome-wide significance (p = 8.3 x 10(-10)) that alters protein coding of the CYP4F2 gene. We confirmed this result in 588 additional Swedish patients (p<0.0029) and, during our investigation, a second group provided independent confirmation from a scan of warfarin-metabolizing genes. We also thoroughly investigated copy number variations, haplotypes, and imputed SNPs, but found no additional highly significant warfarin associations. We present power analysis of our GWAS that is generalizable to other studies, and conclude we had 80% power to detect genome-wide significance for common causative variants or markers explaining at least 1.5% of dose variance. These GWAS results provide further impetus for conducting large-scale trials assessing patient benefit from genotype-based forecasting of warfarin dose.

Project description:BACKGROUND:The anticoagulation of atrial fibrillation catheter ablation during the perioperative stage does matter and should be treated with discretion. We aimed to assess impact of three important genes participating in vitamin K cycle (i.e. VKORC1 rs9923231, CYP4F2 rs2108622 and NQO1 rs1800566) on the daily stable warfarin dose requirement in Sichuan Han Chinese patients with catheter ablation of atrial fibrillation. METHODS:A total of 222 atrial fibrillation patients taking stable warfarin therapy after catheter ablation operation were enrolled in this study. The study population included had high (?2) risk according to the CHA2DS2-VASc risk score. Genotypes of VKORC1 rs9923231, CYP4F2 rs2108622 and NQO1 rs1800566 were analyzed by using the polymerase chain reaction restriction fragment length polymorphism method (PCR-RFLP). Multiple linear regression analysis was applied to depict the impact of VKORC1 rs9923231, CYP4F2 rs2108622 and NQO1 rs1800566 on the daily stable warfarin dose requirement. RESULTS:Carriers of VKORC1 rs9923231 AG/GG genotypes required significantly higher warfarin dose (3.03?±?0.28 mg/day, 7.19 mg/day, respectively) than AA carriers (2.52?±?0.07 mg/day; P <?0.001). Carriers of CYP4F2 rs2108622 CT/TT genotypes required significantly higher warfarin dose (3.38?±?0.22 mg/day, 2.79?±?0.19 mg/day, respectively) than CC carriers (2.41?±?0.08 mg/day; P?<?0.001). However, the warfarin dose for carriers of NQO1 rs1800566 CT/TT genotypes (2.46?±?0.24 mg/day, 3.01?±?0.27 mg/day, respectively) was not significantly higher than that for the CC carriers (2.33?±?0.1 mg/day). The multiple linear regression model including genotypes and demographic characteristics, could explain 20.1% of individual variations in the daily stable warfarin dose in Sichuan Han Chinese. VKORC1 rs9923231 contributed most (15%) to the individual variations in daily stable warfarin dose, while CYP4F2 rs2108622 contributed least (3%). CONCLUSION:NQO1 rs1800566 is not a significant genetic factor of warfarin dose for Han Chinese, whereas VKORC1 rs9923231 and CYP4F2 rs2108622 are significant genetic factors, which could explain 15% and approximately 3% of individual variations in the daily stable warfarin dose respectively.

Dataset Information

Genetic variation of VKORC1 and CYP4F2 genes related to warfarin maintenance dose in patients with myocardial infarction.

Publications

Genetic variation of VKORC1 and CYP4F2 genes related to warfarin maintenance dose in patients with myocardial infarction.

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