中国汉族人群CYP3A4基因变异对华法林初始抗凝治疗反应性的影响

Influence of cytochrome P-450 3A4 genetic variants on warfarin response during initiation of therapy in Chinese Han population

目的探讨细胞色素P450酶3A4基因(cytochrome P-450 3A4,CYP3A4)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年至2008年在广东省人民医院行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可能相关的CYP3A4的2个SNPs多态性位点(rs2242480、rs2246709),采用SNaPshot进行基因单核苷酸多态性(SNP)的检测,并按基因型分组,分别比较CYP3A4不同基因型间华法林日平均剂量、凝血酶原时间国际标准化比值(prothrombin time-internationalnormalized ratio,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。结果在华法林初始治疗的20 d内,华法林日剂量在男性明显高于女性,差异有统计学意义[(2.92±1.18)mg/dvs.(2.64±0.98)mg/d,P<0.05],而PT-INR达到目标值(>1.8)平均需要时间和初始治疗阶段过度抗凝的比率在男女之间比较,差异无统计学意义(P>0.05)。CYP3A4不同基因型之间华法林日剂量、达标时间和过度抗凝比率比较,差异均无统计学意义(P>0.05)。结论 CYP3A4基因变异对中国汉族人群初始治疗20 d内的华法林日剂量无明显影响,常规剂量给药方案在服药初期CYP3A4突变个体出血风险无明显增加。

Objectives To investigate contributions of genetic variants of cytochrome P-450 3A4（CYP3A4） in the anticoagulation response during the initiation of warfarin therapy in Chinese Han population.Methods Subjects included 798 Chinese Han patients who received long-term warfarin anticoagulant therapy orally after valve replacement in Guangdong General Hospital between 2000 and 2008.By selecting and analyzing the 2 single nucleotide polymorphism（SNP）loci（rs2242480 and rs2246709） of CYP3A4 that were possibly correlated with warfarin pharmacokinetics through literature retrieval,we compared the differences of warfarin steady-state dose requirement,prothrombin time-international normalized ratio（PT-INR） within the therapeutic range and percentage of the INR of more than 3.5 between the subgroups which were divided into according to genotype.SNaPshot technique was used to detect gene SNPs;Hardy-Weinberg genetic equilibrium test was used to test population representativeness.Results After the first 20 days of warfarin therapy in Chinese Han population,warfarin dose in male was significantly higher than that in female[（2.92±1.18） mg/d vs.（2.64±0.98）mg/d,P0.05].However,no significant diferences were shown in PT-INR within the therapeutic range and percentage of overanticoagulation between male and female（P0.05）.There were no significant influences on the required warfarin dose,PT-INR within the therapeutic range and percentage of overanticoagulation between CYP3A4 genotypes after the first 20 days of therapy in Chinese Han population（P0.05）.Conclusions Genetic polymorphism of CYP3A4 was not associated with influenceon warfarin dose and high risk of bleeding in Chinese Han population.