老年房颤患者VKORC1和CYP2C9基因多态性对华法林代谢和药效的影响

目的：探讨维生素K环氧化物还原酶复合物1基因（VKORC1）1639G／A（rs9926231）与细胞色素P450酶2C9基因（CYP2C9）1061A／C（rs1057910）多态性对中国汉族老年房颤患者华法林代谢和药效的影响。方法：用PCR—RFLP技术检测248例≥60岁房颤患者及262例≥60岁健康对照者的VKORC1—1639G／A、CYP2C91061A／C基因多态性。用HPLC法检测190例口眼华法林14d后国际标准化比值（1NR）达标1．5～3．0患者血药浓度，比较华法林代谢的药效差异。结果：两组-1639G／A与1061A／C各基因型分布差异无统计学意义（P〉0．05）；INR达标组1061AA型比AC＋CC型华法林维持剂量高、INR值低（P〈0．05），1639AA型比GA＋GG型华法林维持剂量低（P〈0．05）；调整体表面积和剂量后，1061AC＋CC型华法林血药浓度高于AA型（P〈0．05）；调整体表面积、剂量及血药浓度后，-1639AA型INR大干GA＋GG型（P〈0．01）。结论：对中国老年房颤患者来说，VKORC1及CYP2C9基因多态性可能影响华法林药效；VKORC1多态性可能是中国汉族人群华法林维持剂量较低的原因之。

Effects of VKORC1 and CYP2C9 Gene Polymorphisms on Metabolism and Pharmacodynamics of Warfarin in Elderly with Atrial Fibrillation

ABSTRACT Aim： To investigate the effect of vitamin K epoxide reductase （VKORC 1）-1639 G/A（rs9926231） and cytochrome P-450 2C9 （CYP2C9）1061A/C （rs1057910） polymorphisms on metabolism and pharmacodynamics of warfarin in Han Chinese elderly with atrial fibrillation. Methods： The VKORC1 -1639 G/A, CYP2C9 1061A/C genetic polymorphisms were genotyped with polymerase chain reaction and restriction fragment length polymorphism （PCR-RFLP） in 248 Han Chinese patients （more than 60 years old） with atrial fibrillation taking warfarin and 262 healthy control. Plasma warfarin concentration of 190 patients with the INR target value （1.5-3） after 14 days medications were detected with HPLC, and were compared with different VKORC 1 and CYP2C9 genotypes. Results： There were no significant difference in -1639G/A and 1061A/C genotype distribution between the two groups（P〉0.05）; Warfarin maintenance dose was higher in patients with 1061AA than that in 1061AC＋CC [（2.78 ±0.67）mg vs （2.28 ± 0.76）mg, P〈0.05], and INR value was lower too （1.91± 0.35） vs （1.92 ± 0.29）, （P〈0.05）. Warfarin maintenance dose was lower in patients with -1639 AA than that in -1639GA＋GG [（2.52 ±0.63）mg vs （3.09 ± 0.68）mg, P〈0.05]; There was significant difference in warfarin plasma concentration between the patients with 1061AA and with 1061AA＋CC adjusted for body surface area and the dose （P〈0.05）, while there was significant difference in INR value between the patients with -1639AA and with -1639GA＋GG adjusted for body surface area, the dose and plasma concentration （P〈0.01）. Conclusion： As far as elderly patients with atrial fibrillation are concerned, VKORC1 （rs9926231） and CYP2C9 （rs1057910） polymorphisms can affect the pharmacodynamics of warfarin. The maj or genotype of VKORC 1-1639（AA） may account for the universal lower warfarin dosage applied in Chinese Han population.