Influence of Genetic Polymorphisms and Non-Genetic Factors upon Warfarin Maintenance Dose in Japanese Elderly Patients

Abstract

The influence of genetic polymorphisms and non-genetic factors upon warfarin maintenance dose was investigated in elderly Japanese patients. Blood sample were collected and demographic and clinical data including age, sex, weight, height, warfarin dose, and prothrombin time expressed as the international normalized ratio (INR) were obtained from 104 unrelated Japanese patients aged from 44 to 94 years. Plasma concentration of S-warfarin was quantified and genetic polymorphisms of VKORC1, CYP2C9 and CYP2C19 were determined. The warfarin dose was significantly higher in men than in women (2.7 vs 2.3mg/d, respectively) although INR was not different significantly. The dose correlated inversely with age and positively with height, weight and body surface area (BSA). Thus, the dose per BSA was not different between males and females, indicating that the gender difference in warfarin dose might be attributed to difference in body size. Both the VKORC1 and CYP2C9 genotypes significantly influenced the dose per BSA. The dose per BSA was higher in patients with the VKORC1-1639GA (n=17) than those with the-1639AA genotype (n=87). The dose per BSA was lower in patients with CYP2C9*1/*3 (n=9) than in those with CYP2C9*1/*1 (n=95), but was not influenced by the CYP2C19 genotype. Warfarin dose per BSA, INR and plasma concentration of S-warfarin correlated significantly with one another. Step-wise regression model for the warfarin maintenance dose indicated significant contributions from the VKORC1 genotype, age and weight. In conclusion, warfarin dose should be adjusted according to the VKORC1 genotype, age and weight to improve safety and efficacy of treatment.