CYP2C9与VKORC1基因变异对华法林初始抗凝治疗反应性的影响

Impact of CYP2C9 and VKORC1 polymorphism on warfarin response during initiation of therapy

目的 探讨细胞色素P450酶2C9基因（CYP2C9）与维生素K环氧化物还原酶复合物1基因（VKORCI）多态性对中国汉族人华法林初始抗凝治疗反应性的影响。方法入选2000-2008年广东省人民医院瓣膜置换术后长期口服华法林抗凝治疗的中国汉族患者798例，通过文献检索，选取与华法林药动学和药效学可能相关的CYP2C9的6个单核苷酸多态性（SNP）位点[rs12572351G〉A、rs9332146G〉A、rs4917639G〉T、rs1057910A〉C（CYP2C9’3）、rs1934967G〉T、rs1934968G〉A】和VKORC1的3个位点[rs9923231C〉T（．1639G〉A）、rs2359612G〉A、rs10871454C〉T]，采用SNaPshot进行基因SNP的检测，并按基因型分组，分别比较CYP2C9和VKORC1不同基因型间华法林稳态剂量、PT-INR达标时间和过度抗凝发生率的差异。群体代表性检验采用Hardy．Weinberg遗传平衡检验。结果CYP2C9’3基因变异对中国汉族人群初始治疗28d的华法林剂量无明显影响，常规剂量给药方案在服药初期CYP2C9’3突变个体有较高的出血风险。中国人群VKORC1rs10871454G〉A和VKORC1—1639G〉A等位基因突变频率分别为92．04％和88．03％，两者之间具有连锁性。VKORC1rs10871454基因变异与中国汉族人群初始治疗28d的华法林剂量具有一定的相关性，基因突变个体对华法林的需求剂量降低。VKORC1-1639基因多态性与华法林的起效时间的长短和过度抗凝等不良反应的发生率存在相关性。服用同等剂量的华法林，基因突变个体的起效时间更快，同时具有较高的出血风险。结论CYP2C9和VKORC1基因多态性检测结合临床数据为指导临床合理使用华法林、避免和减少出血等不良反应的发生提供了新的方法。

Objective To investigate potential contributions of genetic variants of cytochrome P-450 2C9 （CYP2C9） and vitamin K expoxide reductase （VKORC1） to the anticoagulation response during the initiation of warfarin therapy in the Han Chinese population. Methods A total of 798 Han Chinese patients received long-term warfarin anticoagulant therapy orally after valve replacement in our hospital between 2000 and 2008 were included in this study. Nine single nucleotide polymorphism （SNP） loci [ rs12572351 G 〉 A, rs9332146 G 〉 A, rs4917639 G 〉 T, rs1057910 A 〉 C （CYP2C9 ＊ 3）, rs1934967 G 〉 T, rs1934968 G 〉 A, rs9923231 C 〉T （VKORC1-1639 G 〉 A）, rs2359612 G 〉 A and rs10871454 C 〉 T] in 2 genes including CYP2C9 and VKORC1, which were possibly correlated with warfarin pharmacokinetics and pharmacodynamics through literature retrieval, were selected and analyzed Warfarin steady-state dose requirement, time to the INR （ the international normalized ratio ） within the therapeutic range and percent of the INR of more than 3.5 were compared among genotype subgroups. SNaPshot technique was used to detect gene SNPs; Hardy-Weinberg genetic equilibrium test was used to test population representativeness. Results CYP2C9 ＊3 genotype did not affect the required warfarin dose while it was associated with increased risk of bleeding when treated with routine dosage regimen during the initiation of treatment. The allelic mutation frequency at VKORC1 gene rs10871454G 〉 A and VKORC1- 1639G 〉 A SNP loci was 92. 04% and 88.03% , respectively and rs10871454 was in perfect linkage disequilibrium with- 1639. Patients with VKORC1 rs10871454 genetic mutation required lower warfarin dose in the first 28 days of therapy. VKORCl-1639 genetic polymorphism was also associated with shorter time to the INR within the therapeutic range and increased risk of over-anticoagulation. Conclusion Detecting genetic polymorphism of CYP2C9 and VKORC1 could guide clinical use of warfarin to reduce the risk of adverse reactions including bleeding in patients receiving chronic anticoagulation therapy.