检测VKORC1、CYP2C9^(*)3基因多态性指导急性肺血栓栓塞症患者华法林抗凝治疗的价值

Significanceof VKORC1 and CYP2C9^(*)3 gene polymorphisms detection in warfarin anticoagulant therapy for patients with acute pulmonary thromboembolism

目的探讨维生素K环氧化物还原酶复合物1(VKORC1)、细胞色素P450酶2C9^(*)3(CYP2C9^(*)3)基因多态性检测在指导急性肺血栓栓塞症(PTE)患者接受华法林抗凝治疗中的临床价值。方法回顾性收集2016年1月~2018年12月四川大学华西医院呼吸与危重症医学科住院接受华法林抗凝治疗的411例成人PTE患者为研究对象。根据是否行VKORC1、CYP2C9^(*)3基因多态性检测并据此制定华法林初始剂量及调整方案分为指导组(基因检测指导组,n=119)和对照组(常规处理组,n=292)。以开始使用华法林到国际标准化比值(INR)第一次达标(2-3)的时间(d)为主要观察指标;以稳定时(INR 2-3)的华法林维持剂量为次要观察指标,比较两组差异。随访两组自接受华法林抗凝开始到第6个月末时的不良反应。结果基因多态性,VKORC1以AA野生型多见(n=89,74.8%);其次为GA杂合突变型(n=29,24.4%);纯合突变GG型仅1例(0.8%)。CYP2C9^(*)3野生型(AA型)为106例(89.1%);杂合突变(AC型)13例(10.9%)。从两个基因多态性组合看,VKORC1 AA型合并CYP2C9^(*)3 AA型81例,占68.1%,即大部分患者两个基因均为野生型;其次为VKORC1 GA型合并CYP2C9^(*)3 AA型24例(20.2%);VKORC1、CYP2C9^(*)3均突变的5例(4.20%)。指导组INR达到目标范围的时间为(7.96±4.02)d,对照组INR达标的时间为(7.68±3.58)d,二者无统计学差异(P>0.05);指导组达到目标INR的华法林维持剂量为(5.30±0.99)mg,对照组的华法林维持剂量为(5.22±0.64)mg,二者无显著性差异(P>0.05)。两组患者出现死亡、大出血、新发血栓的不良事件发生率均无统计学意义(均P>0.05)。结论VKORC1、CYP2C9^(*)3基因多态性检测在指导急性PTE患者接受华法林抗凝治疗中的意义有限。

Objective To investigate the clinical significance of Vitamin K epoxide reductase complex 1(VKORC1)and Cytochrome P4502C9^(*)3(CYP2C9^(*)3)gene polymorphismsdetection in guiding patients with acute pulmonary thromboembolism(PTE)to receive warfarin anticoagulant therapy.Methods Non-high-riskpatients with acute PTE who were treated with warfarin anticoagulant therapy in West China Hospital of Sichuan University were retrospectively collected.According to whether VKORC1 and CYP2C9^(*)3 gene polymorphisms were detected and the initial dose and adjustment scheme of warfarin were formulated,they were divided into experimental group(gene detection guidedgroup,n=119)and control group(conventional treatment group,n=292).The primary endpoint was the interval time(d)from the beginning of warfarin use to achieving the first standard of international normalized ratio(INR)(2-3).The secondary endpoint was the maintenance dose of warfarin.Results AA wild type was the mainly genetic polymorphism of VKORC1(n=89,74.8%),followed by GA heterozygous mutation(n=29,24.4%).Homozygous mutation GG was found only in 1 case(0.8%).There were 106 cases(89.1%)of CYP2C9^(*)3 wild type(AA type)and 13 cases(10.9%)of heterozygous mutation(AC type).VKORC1 AA combined with CYP2C9^(*)3 AA were detected in 81 cases(68.1%),followed by 24 cases(20.2%)of VKORC1 GA combined with CYP2C9^(*)3 AAand 5 cases(4.20%)with VKORC1 and CYP2C9^(*)3 mutation.The interval time(d)from the beginning of warfarin use to achieving the first standard INR in the experimental group was(7.96±4.02)d,and that in the control group was(7.68±3.58)d.There was no significant difference between the two groups(P=0.494).Moreover,the maintenance dose of warfarin in the experimental group was(5.30±0.99)mg,and that in the control group was(5.22±0.64)mg,with no significant difference(P=0.317).The proportion of death,massive hemorrhage and new thrombosis in the two groups were similar as well(P>0.05).Conclusion The significance of VKORC1 and CYP2C9^(*)3 gene polymorphisms detection in guiding acute PTE patients to receive warfarin anticoagulant therapy was limited.