细胞色素P450 2C9和维生素K环氧化物还原酶复合体1基因多态性对非瓣膜性心房颤动患者华法林维持剂量的影响

Effects of cytochrome P450 2C9 and vitamin K epoxide reductase complex 1 genetic polymorphisms on maintenance dosage of warfarin in patients with non-valvular atrial fibrillation

目的 探讨细胞色素P450（CYP）2C9和维生素K环氧化物还原酶复合体1（VKORC1）基因多态性对非瓣膜性心房颤动患者华法林维持剂量的影响。方法 选择2015年1月至2016年9月于上海交通大学医学院附属新华医院心内科病房住院的非瓣膜性心房颤动并服用华法林的患者100例。采用等位基因特异性引物结合实时荧光聚合酶链反应法测定100例非瓣膜性心房颤动患者CYP 2C9和VKORC1基因多态性。收集患者性别、年龄、体质量、华法林稳定维持剂量、凝血酶原时间国际标准化比值等指标做分析。结果 100例非瓣膜性心房颤动患者的CYP 2C9基因检测有93例野生纯合体型、7例突变杂合体型，VKORC1基因检测有89例野生A/A型、11例突变A/G型。CYP 2C9杂合体型患者较野生纯合体型患者所需华法林稳态剂量小［（1.8±0.8）mg比（2.4±1.0）mg］，VKORC1基因A/A型较A/G型华法林稳态剂量小［（2.2±1.0）mg比（3.1±0.8）mg］，男性患者所需的华法林稳定维持剂量高于女性患者［（2.6±1.2）mg比（2.1±0.8）mg］，差异均有统计学意义（均P〈0.01）。随着患者年龄的增加，50~59岁、60~69岁、70~79岁患者所需华法林维持稳态剂量呈降低趋势［（2.8±1.6）、（2.4±0.9）、（2.2±0.8）、（2.1±0.9）mg］。结论 CYP 2C9和VKORC1基因多态性与华法林维持剂量的个体间差异有关系。年龄和性别是影响华法林维持量的重要因素。

Objective To investigate the effect of cytochrome P450 2C9（CYP 2C9） and vitamin K epoxide reductase complex 1（VKORC1） genetic polymorphisms on maintenance dosage of warfarin in patients with non-valvular atrial fibrillation. Methods Genotypes of CYP 2C9 and VKORC1 in 100 patients with non-valvular atrial fibrillation were detected by allele-specific real-time fluorescence polymerase chain reaction. Sex, age, weight, maintenance dose of warfarin and prothrombin time international normalized ratio were analyzed. Results Genetic test of CYP 2C9 showed 93 wild homozygotes and 7 mutant heterozygotes. Genetic test of VKORC1 showed 89 wild A/A types and 11 mutant A/G types. The maintenance dose of warfarin in CYP 2C9 mutant types was significantly less than that in wild types［（1.8±0.8）mg vs （2.4±1.0）mg］（P＜0.01）. The maintenance dose of warfarin in VKORC1 A/A types was significantly less than that in A/G types［（2.2±1.0）mg vs （3.1±0.8）mg］（P＜0.01）. The maintenance dose of warfarin in male was significantly less than that in female［（2.6±1.2）mg vs （2.1±0.8）mg］（P＜0.01）. There was a decreasing trend of warfarin maintenance dose among 40-49, 50-59, 60-69, 70-79 age groups［（2.7±2.5）, （2.8±1.6）, （2.4±0.9）, （2.2±0.8）, （2.1±0.9）mg］. Conclusions CYP 2C9 and VKORC1 genetic polymorphisms are associated with the individual difference of warfarin maintenance dosage. Age and sex are influence factors of warfarin maintenance dosage.