VKORC1, CYP2C9 Polymorphisms and clotting factors associated with warfarin maintenance dose

Abstract

There are high intraindividual, interindividual and interethnic variabilities in warfarin dosing. It is difficult to adjust or to predict the appropriate dose for individual patient. Aim of this study was to investigate the association of CYP2C9, VKORC1 genotypes and clotting factors on warfarin maintenance dose and to establish the equation to predict the maintenance dose of warfarin in Thai population. Genotypes of CYP2C9*2, CYP2C9*3, VKORC1 C1173T and VKORC1 G-1639A were performed in 107 Thais outpatients who were taking stable dose of warfarin for at least 2 months at The King Chulalongkorn Memorial Hospital. Most of allele frequency in Thais was CYP2C9*1 (98.0%) while no CYP2C9*2 was found in Thai population. Allele frequency of CYP2C9*3 was 2.0% [95%CI 1.0%-5.0%]. VKORC1 haplotype group A (1173 TT and -1639AA) was the major group (74.8%, 95%CI 69.1%-79.8%) in Thais. Mean weekly warfarin dose in CYP2C9*3 group was significantly lower than those in CYP2C9*1 group, p=0.019 [95%CI 0.040-0.448]. Warfarin clearance in CYP2C9*3 group was significantly lower than those in CYP2C9*1 group, p=0.014 [95%CI 0.005-0.044]. Furthermore, the mean weekly warfarin doses in VKORC1 AA genotypes were significantly lower than those in VKORC1 BB and AB genotypes, p=0.025 and p<0.0001, respectively. Contribution of CYP2C9*3 and VKORC1 genotypes account for 48% of variance in warfarin dose. Using forward stepwise multiple linear regression, the model which included CYP2C9*3, VKORC1, age, weight and INR:total warfarin concentration could explain 59.5 % of the variance in warfarin maintenance dose. Genetic factors played the important role on the interindividual variation in warfarin maintenance dose in Thai population.