VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients

Objectives: To compare the genetic and clinical factors that cause large interpatient variability and ethnic differences in warfarin efficacy, we investigated variations of the VKORC1, CYP2C9, and CYP2C19genes in Japanese subjects. Furthermore, we evaluated the genetic variations and clinical data as contributors of variation in warfarin maintenance dose. Methods. Gene variations of VKORC1, CYP2C9, and CYP2C19 in 125 patients treated with warfarin and 114 healthy subjects were analyzed. The daily dose of warfarin, concentrations of S- and R-warfarin in plasma, and prothrombin time expressed as the international normalized ratio were used as the pharmacokinetic and pharmacodynamic indices. Data were evaluated by a multivariate analysis method. Results: Three missense mutations (47 G > C, 113 A > C, and 1338 A > G) in VKORC1 were newly identified in the Japanese population. The 113 A > C (Asp38Ser) variant decreased the warfarin dose requirement from 3.33 +/- 1.54 mg/d (n = 122) to 1.5 mg/d (n = 1). The variants -1639 G > A in the 5'-upstream region, 1173 C > T in intron 1, and 1542 G > C in intron 2 were in complete linkage disequilibrium, and the frequency of the -1639 G>A variation was only 0.8%, which contrasts with the frequency (39.8%-45.8%) reported previously for white persons. The dose of warfarin was larger in the VKORC1 -1639 GA genotype group (4.55 +/- 1.75 mg/d, P < .001) than in the -1639 AA group (2.94 +/- 1.15 mg/d). The mean daily dose of warfarin was lower in subjects with CYP2C9*1/*3 (1.86 +/- 0.80 mg/d, P = .007) than in subjects with CYP2C9*1/*1 (3.36 +/- 1.43 mg/d). When the relative contributions of the VKORC1 variants, CYP2C9*2, CYP2C9*3, CYP2C19*2, and CYP2C19*3, as well as the clinical characteristics of the patients, diagnoses, and concurrent medications, were compared, the VKORC1 - 1639 GA genotype group accounted for 16.5% and CYP2C9 variants accounted for 13.4% of variation in warfarin dose. Conclusion: The ethnic difference in warfarin maintenance dose was mainly dependent on the linked VKORC1 variants. Genotyping of - 1639 G > A of the VKORC1 gene could be clinically important for predicting individual variability in anticoagulant responses to warfarin.