Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups

Abstract

Warfarin-dosing algorithms incorporating CYP2C9 and VKORC1 ؊1639G>A improve dose prediction compared with algorithms based solely on clinical and demographic factors. However, these algorithms better capture dose variability among whites than Asians or blacks. Herein, we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1 ؊1639G>A among Asians (n ‫؍‬ 1103), blacks (n ‫؍‬ 670), and whites (n ‫؍‬ 3113).Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes on warfarin dose used both univariate and multivariable linear regression. VKORC1 ؊1639G>A and 1173C>T individually explained the greatest variance in dose in all 3 racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction.VKORC1 explained greater variability in dose among whites than blacks and Asians. Differences in the percentage of variance in dose explained by VKORC1 across race were largely accounted for by the frequency of the ؊1639A (or 1173T) allele. Thus, clinicians should recognize that, although at a population level, the contribution of VKORC1 toward dose requirements is higher in whites than in nonwhites; genotype predicts similar dose requirements across racial groups. (Blood. 2010;115(18):3827-3834) IntroductionWarfarin, the most commonly prescribed anticoagulant, exhibits large interpatient variability in dose requirements. Patient-specific factors (eg, age, body size, race, concurrent diseases, and medications) explain some of the variability in warfarin dose, but genetic factors influencing warfarin response explain a significantly higher proportion of the variability in dose. 1 Candidate-gene association studies 2-22 have identified 2 genes responsible for the main proportion of the genetic effect: CYP2C9, which codes for the enzyme cytochrome P450 2C9 that metabolizes S-warfarin, 23,24 and VKORC1, which codes for warfarin's target, vitamin K epoxide reductase. 25,26 The influence of CYP2C9 and VKORC1 has also been confirmed by genome-wide association studies among whites. 27,28 These studies suggest that identification of common variants in other genes exhibiting influence of magnitude similar to that of CYP2C9 and VKORC1 is unlikely in whites. The most influential CYP2C9 polymorphisms are nonsynonymous coding variants resulting in reduced enzyme activity and decreased metabolic capacity. [29][30][31] In contrast, common VKORC1 variants associated with warfarin dose are noncoding polymorphisms, the effects of which are thought to be mediated through differential expression of the VKOR protein. 32 These polymorphisms are within a region of strong linkage disequilibrium (LD) among patients of European ancestry; thus, they may all point to the same common causal polymorphism. 10,14 However, neither the causative VKORC1 polymorphism nor the molecula...

Pharmacogenomics and personalized medicine: a review focused on their application in the Chinese population

“…The most common VKORC1 variant is a noncoding variant (VKORC1 -1639 G>A, rs9923231) that lies in the promoter region of VKORC1. The -1639 G allele has decreased enzyme activity, so individuals who carry the G allele require higher warfarin doses than those with the A allele [77,78] . CYP4F2 is another genetic factor in warfarin processing.…”

Genetic and Non-Genetic Factors Association with Warfarin Long Term Therapy Stability in Sudan

“…From these results, given the smaller range of variant allele frequency for CYP2C9 to that of VKORC1, it is apparent that the association in warfarin therapy stability is larger for VKORC1 than for CYP2C9 29,30 . By taking a general look at the ethnicity versus frequencies of both genes, we found that 22% of all Sudanese patients were without any of the variant alleles of both CYP2C9*2 and VKORC1-1639G>A, that means having neither heterozygous nor homozygous mutant genotypes of the tow genes studied.…”

The fallacy of racial pharmacogenomics

“…We also retrieved American Blacks from the Southwest USA (ASW -48 individuals) and American Whites from Utah, USA (CEU -112 individuals). In all groups we ascertained genotypes at the rs9923231 SNP, the same that, according to Limdi et al (13), explained the greatest variance in warfarin dose.…”