CYP2C9与VKORC1基因变异对华法林初始抗凝治疗反应性的影响

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( VKORC1)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CYP2C...

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

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),rsl934967 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 genotyps 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 with1639.Patients with VKORC1 rs10871454 genetic mutation required lower warfarin dose in the first 28 days of therapy.VKORC1-1639 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.