Influence of clinical and genetic factors on warfarin dose requirements among Japanese patients

Objective The aim of this study was to investigate the influence of clinical and genetic factors on warfarin dose requirements in the Japanese population. Methods We enrolled 125 patients on stable warfarin anticoagulant therapy with an international normalized ratio maintained between 1.5 and 3.0. PCR-based methods were performed to analyze genetic polymorphisms in the genes pharmacokinetically and pharmacodynamically related to warfarin reactions, including cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), gamma-glutamyl carboxylase (GGCX) and factor VII (FVII). Results The presence of CYP2C9*3 and VKORC1-1639G>A had a significant impact on the mean maintenance dose of warfarin (CYP2C9*1/*1 2.74 ± 1.24 mg/day vs. *1/*3 and *3/*3 1.56 ± 0.85 mg/day, P = 0.009; VKORC1-1639AA 2.42 ± 0.95 mg/day vs. GA 3.71 ± 1.43 mg/day vs. GG 7.25 ± 0.35 mg/day, P A explained 54.8% of the variance in warfarin dose requirements. Conclusions The influences of CYP2C9*3 and VKORC1-1639G>A on the maintenance dose of warfarin were well-defined in Japanese patients, while polymorphisms of GGCX and FVII did not affect it. The model established in this study might provide us most likely individual maintenance dose based on clinical and genetic backgrounds.