Genotypes of vitamin K epoxide reductase, γ-glutamyl carboxylase, and cytochrome P4502C9 as determinants of daily warfarin dose in Japanese patients

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), gamma-glutamyl carboxytase (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. (C) 2006 Elsevier Ltd. All rights reserved.