Effect of CYP2C9 and VKORC1 gene polymorphisms on warfarin anticoagulation / 第二军医大学学报

ABSTRACT

Objective To evaluate the effect of gene polymorphisms in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) on warfarin maintenance dose and plasma concentration in Chinese Han population in Shanghai. Methods A total of 226 patients who underwent oral warfarin anticoagulation therapy after valve replacement under cardiopulmonary bypass were enrolled in this study. The CYP2C9 1061A/C and VKORC1 -1639 G/A and 1173C/T genotypes were determined by pyrosequencing. The plasma level of warfarin was determined by the UPLC/MS-MS method. The patients were divided into different groups based on genotypes, sex and age. The average daily dose of warfarin and plasma concentration of warfarin were compared between different groups, and the contributions of genotype, plasma concentration, sex and age to warfarin daily dose were calculated. Results Maintenance dose of warfarin in patients withCYP2C9 1061A/C AA type was significantly higher than those with CYP2C9 1061A/C AC type (P<0.05). Maintenance dose of warfarin in patients with VKORC1 -1639G/A AG type was significantly higher than those with VKORC1 -1639G/A AA type (P<0.01). Maintenance dose of warfarin in patients with VKORC1 1173C/T CT type was significantly higher than those with VKORC1 1173C/T TT type (P<0.01). Significant differences of plasma warfarin concentration were also observed between VKORC1 -1639 G/A AA and AG as well as 1173C/T TT and CT genotypes (P<0.01), but not in those with CYP2C9 1061A/C genotypes. The average daily dose of warfarin was significantly higher in male patients than in females (P<0.05). The maintenance dose of warfarin was also significantly higher in patients under 60 years old than those aged above 60 years (P<0.05). CYP2C9 1061A/C, VKORC1 -1639G/A, and VKORC1 1173C/T gene polymorphisms, plasma concentration, age and gender accounted for 7.2%, 29.1%, 30.4%, 6.7%, 1.6% and 1.4% of warfarin dose variance, respectively; and multi-factor combination accounted for totally 47.2% of warfarin dose variance. Conclusion CYP2C9 1061A/C, VKORC1 -1639 G/A and VKORC1 1173C/T genotypes are associated with lower levels of warfarin dose. VKORC1 -1639G/A and 1173C/T genotypes also have a close relationship with warfarin plasma concentration. Sex and age are the important non-genetic influencing factors on warfarin daily dose.