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 multi variable 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.

Figure 1

Effect of VKORC1 −1639G>A minor allele frequency in explaining warfarin dose variability at the population level. Results of a simulation study showing the influence of the frequency of the A allele for −1639G>A on the amount of variance in warfarin dose explained (R²). Quartiles and upper and lower 2.5th percentiles of the distribution of R² values from the simulation are plotted as a function of minor allele frequency. The highest variability in dose explained would occur in a population with an A allele frequency of approximately 60% to 70%. The actual R² estimates for each racial group in the IWPC data are plotted as squares at the observed MAF for each group.

Figure 2

Worldwide haplotype distribution. The frequencies of 7 globally distributed haplotypes for 6 SNPs in the VKORC1 gene are represented by pie charts over the country of origin of population samples from which they were derived. The SNPs are listed in the order in which they occur along the VKORC1 gene: −1639G>A, 497T>G, 1173C>T, 1542G>C, 2255C>T, 3730G>A. All haplotypes occurring at frequencies of less than 2.5% in all population samples tested are grouped together in the “Other” category. For the United States, the population samples are broken down into white (W), black (B), and Mexican American (MA) subgroups and by the study under which they were collected: International Warfarin Pharmacogenetics Consortium or National Health and Nutrition Examination Survey III. Detailed data underlying this figure can be found in supplemental Table 5.