VKORC1及CYP2C9基因多态性和连锁不平衡 对华法林临床应用的影响  

Effect of VKORC1 and CYP2C9 gene polymorphism and linkage disequilibrium on the clinical application of warfarin

作　　者：胡蓉[1] 谢骊[2] 王彦[1] 程君[1] 李真真[1] HU Rong;XIE Li;WANG Yan;CHENG Jun;LI Zhen-zhen(Department of Pharmacy,Shanghai Baoshan Branch of Shanghai First People's Hospital,Shanghai 200940;Department of Clinical Laboratory,Shanghai Baoshan Branch of Shanghai First People's Hospital,Shanghai 200940)

机构地区：[1]上海市第一人民医院宝山分院药剂科,上海200940 [2]上海市第一人民医院宝山分院检验科,上海200940

出　　处：《中南药学》2019年第2期294-298,共5页Central South Pharmacy

基　　金：上海市卫生和计划生育委员会项目(编号:20164Y0176)

摘　　要：目的调查维生素K环氧化物还原酶复合物亚基1(VKORC1)、细胞色素P450(CYP)2C9和CYP2C19的等位基因分布,不同等位基因变异的贡献和可能的基因-基因相互作用对华法林治疗的影响。方法共纳入492名患者,并对VKORC1、CYP2C9和CYP2C19的单核苷酸多态性进行基因分型。结果 CYP2C9*1等位基因与CYP2C19*2和CYP2C19*17(D'=1)完全连锁不平衡。表达为VKORC1 GA、VKORC1 AA、CYP2C9*2和CYP2C9*3的等位基因变异患者需要比表达为VKORC1 GG或CYP2C9*1的野生型患者更低的华法林剂量。华法林稳定剂量和INR> 5事件的CYP2C19等位基因各种变异之间差异无统计学意义。表达为CYP2C19*2/*2、CYP2C19*2/*17和CYP2C19*17/*17基因型患者倾向于比CYP2C19*1/*1基因型患者需要更高的华法林剂量。逐步回归分析显示,年龄和性别是华法林剂量的显著影响因素。在单变量一般线性模型分析中检测到CYP2C9和VKORC1对华法林剂量和INR> 5事件没有统计学意义上的相互作用。结论 VKORC1和CYP2C9的基因多态变体独立影响华法林剂量,而CYP2C19不影响华法林治疗。Objective To investigate the allelic distribution of vitamin K epoxide reductase complex subunit 1(VKORC1), cytochrome P450(CYP) 2 C9 and CYP2 C19, the effect of different alleles and possible gene-gene interactions on warfarin therapy. Methods A total of 492 patients were included into this study, and the single nucleotide polymorphisms of VKORC1, CYP2 C9 and CYP2 C19 were genotyped. Results The CYP2 C9*1 allele was completely unbalanced with CYP2 C19*2 and CYP2 C19*17(D’ = 1). Patients with VKORC1 GA, VKORC1 AA, CYP2 C9*2 and CYP2 C9*3 genetic variants need significantly lower warfarin dose than those with VKORC1 GG or CYP2 C9*1 wild type alleles. There was no significant difference between the amount of warfarin stabilizer and the CYP2 C19 allele variation of the INR >5 event. CYP2 C19*2/*2, CYP2 C19*2/*17 and CYP2 C19*17/*17 genotype patients tend to have higher warfarin dose than CYP2 C19*1/*1 genotype patients. Stepwise regression analysis showed that age and gender were the significant factors on warfarin dose. In the analysis of the univariate general linear model, there was no significant interaction between CYP2 C9 and VKORC1 for the warfarin dose and INR >5 events. Conclusion The polymorphic variants of VKORC1 and CYP2 C9 independently affect the warfarin dose, while CYP2 C19 has no effect on warfarin treatment.

关 键 词：华法林 CYP2C9 VKORC1 CYP2C19 相互作用 

分 类 号：R969.1[医药卫生—药理学]