Genotypes of vitamin K epoxide reductase, γ-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients

Abstract The dose required for the anticoagulant effect of warfarin exhibits large inter-individual variations. This study sought to determine the contribution of four genes, vitamin K epoxide reductase ( VKORC1 ), γ-glutamyl carboxylase ( GGCX ), calumenin ( CALU ), and cytochrome P450 2C9 ( CYP2C9 ) to the warfarin maintenance dose required in Japanese patients following ischemic stroke. We recruited 93 patients on stable anticoagulation with a target International Normalized Ratio (INR) of 1.6–2.6. We genotyped eleven representative single nucleotide polymorphisms (SNPs) in the three genes involved in vitamin K cycle and the 42613A>C SNP in CYP2C9 , known as CYP2C9 ⁎ 3 , and then examined an association of these genotypes with warfarin maintenance doses (mean ± SD = 2.96 ± 1.06 mg/day). We found an association of effective warfarin dose with the − 1639G>A ( p = 0.004) and 3730G>A genotypes ( p = 0.006) in VKORC1 , the 8016G>A genotype in GGCX ( p = 0.022), and the 42613A>C genotype in CYP2C9 ( p = 0.015). The model using the multiple regression analysis including age, sex, weight, and three genetic polymorphisms accounted for 33.3% of total variations in warfarin dose. The contribution to inter-individual variation in warfarin dose was 5.9% for VKORC1 − 1639G>A, 5.2% for CYP2C9 42613A>C, and 4.6% for GGCX 8016G>A. In addition to polymorphisms in VKORC1 and CYP2C9 , we identified GGCX 8016G>A, resulting in the missense mutation R325Q, as a genetic determinant of warfarin maintenance dose in Japanese patients.