Effect Of VKORC1 And CYP2C9 Genetic Polymorphisms On Metabolism And Anticoagulant Action Of Warfarin In Elderly With Atrial Fibrillation.

Objective : This study investigated the effect of vitamin K epoxide reductase (VKORC1) 1639 G/A and cytochrome P-450 2C9 (CYP2C9)1061A/C polymorphisms on metabolism and anticoagulant action of Warfarin in Han Chinese elderly with atrial fibrillation.Methods:1. The VKORC1 1639 G/A, CYP2C9 1061 A/C genetic polymorphisms were detected with polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) in 98 Han Chinese patients over 60 with atrial fibrillation taking Warfarin and 112 healthy controls. The treatment group and control group were further divided respectively into 3 subgroups by genotypes. Statistic analyses were performed using t-test for measurement data, and X2 test or Fisher exact test for count data.2. 70 patients treated with Warfarin reached the target value (INR: 1.5~3) after 14 days medications, plasma Warfarin concentration and INR were tested. Covariance analysis of mixed factors was taken for correction.Results:1. There were no significant difference in age, sex, body surface area between the treatment group and the control group. VKORC1-1639 G/A and CYP2C9 1061A/C genotype distribution were consistent with the Hardy-Weinberg Law (P> 0.05) in both groups, which indicated that study population was a representative sample. There were no significant difference in VKORC1-1639 G/A and CYP2C9 1061 A/C genotype distribution between two groups (P> 0.05).2. Comparison between different CYP2C9 1061 A/C, VKORC1-1639 G/A genotypes among 70 patients treated with Warfarin reached the target value: Warfarin maintenance dose was higher in patients with CYP2C9 1061 AA than CYP2C9 1061 AC + AA (respectively, 2.78±0.67mg and 2.28±0.76mg, p <0.05), and INR value was lower too (1.91±0.35 and 1.92±0.29, p <0.05). Warfarin maintenance dose was lower in patients with VKORC1-1639 G/A AA than VKORC1-1639 G/A AG+GG (respectively, 2.52±0.63mg and 3.09±0.68mg, p <0.05). and INR value was higher too(1.98±0.38 and 1.78±0.19,P<0.05)3. Covariance analysis with body surface area and the dose for covariates showed that: there was significant difference in Warfarin plasma concentration between patients with CYP2C9 1061 AA and with CYP2C9 1061 AA+CC, while there was no significant difference between two groups patients with VKORC1-1639 G/A.4. Covariance analysis with body surface area, the dose and plasma concentration for covariates showed that: there was significant difference in INR value between patients with VKORC1-1639 AA and with VKORC1-1639 AG+GG(respectively, 1.98±0.38 and 1.78±0.19, P<0.05), while there was no significant difference between two groups patients with CYP2C9 1061 A/C. Conclusion:As far as elderly patients with atrial fibrillation are concerned, Warfarin plasma concentration was significantly lower in patients with CYP2C9 1061 AA than with CYP2C9 1061 AC+CC, suggesting that the ones with CYP2C9 1061 AA have faster Warfarin metabolism; and INR value was significantly higher in patients with VKORC1-1639 AA than with VKORC1-1639 AG+GG. VKORC1-1639 AA-type patients was significantly higher than that of INR GG-AG +, suggesting that the ones with VKORC1-1639 AA are more sensitive to Warfarin.