Dataset Information

Evaluation of CYP2C9- and VKORC1-based pharmacogenetic algorithm for warfarin dose in Gaza-Palestine.

ABSTRACT: Aim:To evaluate applicability of CYP2C9*2, *3 and VKORC1-1639G > A based algorithm to predict warfarin stable dose (WSD) in a group of Palestinian patients. Patients & methods:Warfarin doses were retrospectively calculated for 101 Palestinian patients under warfarin therapy using three models. Performance of the three models was assessed in 47 patients found to take WSD. Results:Frequency of CYP2C9*2, *3 and VKORC1-1639G > A alleles is 13.6, 0.0 and 46.5% respectively. The international warfarin pharmacogenetics consortium algorithm was more reliable (MAE = 8.9 ± 1.4; R2 = 0.350) than both the clinical algorithm (MAE = 10.4 ± 1.4; R2 = 0.128;) and the fixed-dose algorithm (MAE = 11.1 ± 1.7). Conclusion:The international warfarin pharmacogenetics consortium algorithm can be reliably applied for predicting the WSD in Palestinian population.

SUBMITTER: Ayesh BM

PROVIDER: S-EPMC5859345 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Evaluation of <i>CYP2C9</i>- and <i>VKORC1</i>-based pharmacogenetic algorithm for warfarin dose in Gaza-Palestine.

Ayesh Basim Mohammad BM Abu Shaaban Ahmed Shaker AS Abed Abdalla Asaf AA

Future science OA 20180110 3

<h4>Aim</h4>To evaluate applicability of <i>CYP2C9*2</i>, <i>*3</i> and <i>VKORC1-1639G > A</i> based algorithm to predict warfarin stable dose (WSD) in a group of Palestinian patients.<h4>Patients & methods</h4>Warfarin doses were retrospectively calculated for 101 Palestinian patients under warfarin therapy using three models. Performance of the three models was assessed in 47 patients found to take WSD.<h4>Results</h4>Frequency of <i>CYP2C9*2</i>, <i>*3</i> and <i>VKORC1-1639G > A</i> alleles ...[more]

PMID: 29568565

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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.

Dataset Information

Evaluation of CYP2C9- and VKORC1-based pharmacogenetic algorithm for warfarin dose in Gaza-Palestine.

Publications

Evaluation of <i>CYP2C9</i>- and <i>VKORC1</i>-based pharmacogenetic algorithm for warfarin dose in Gaza-Palestine.

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