五种基因多态性对华法林用量个体差异影响的研究

Impact of five genetic polymorphisms on inter-individual variation in warfarin maintenance dose

目的探讨维生素K环氧化物还原酶复合体亚单位1基因（vitaminKepoxidereductasecomplexsubunit1，VKORCl）、细胞色素P4502C9基因（cytochromeP4502C9，CYP2C9）、-／-谷氨酰羧化酶基因（gamma—glutamylcarboxylase，GGCX）、微粒体环氧化物水解酶基因（microsomalepoxidehydrolase1，EPHXl）和载脂蛋白E基因（apolipoproteinE，APOE）多态性与个体间华法林稳定剂量差异的关系。方法收集249例已获得华法林稳定剂量患者的临床资料及血样，采用聚合酶链反应-变性高效液相色谱技术，检测5种基因的基因型。比较不同基因型患者间华法林稳定剂量的差异，结合非遗传因素，建立华法林稳定剂量的预测算法。结果5种基因中与华法林稳定剂量相关的有VKORCl、CYP2C9和C,GCX。多元回归分析提示对华法林用量个体差异有显著影响的因素有年龄、体重、VKORCl、CYP2C9和GGCX。根据最佳回归模型得到的华法林稳定剂量预测算法可解释华法林稳定剂量个体差异57．8％的原因。VKORCl，CYP2C9，GGCX，年龄、体重对华法林用量个体差异的贡献分别是30．2％、22．8％、1．5％、4．7％和6．7％。结论遗传因素是影响华法林个体间用量差异的主要因素；华法林稳定剂量预测算法可提高临床上华法林使用的有效性和安全性。

Objective To investigate the effect of genetic polymorphisms in VKORC1, CYP2Cg, GGCX, EPHX1, APOE genes on inter-individual variation in warfarin maintenance dose. Methods Two hundred and forty-nine patients with stable warfarin dose were enrolled in this study, and the clinical data and blood samples of the patients were collected. Genotypes for the 5 genes were determined by using PCR and denaturing high performance liquid chromatography （DHPLC） assay. The warfarin maintenance doses were compared among patients with different genotypes of the 5 genes, and a warfarin stable dosing algorithm was derived based on genetic and non-genetic factors. Results Of the 5 genes, VKORC1, CYP2C9 and GGCX were associated with warfarin stable dose. The multiple linear regression analysis indicated that VKORC1, CYP2C9 and GGCX genes, age and weight, had significant influence on inter- individual variation in warfarin stable dose, which contributed 30.2%, 22.8%, 1.5%, 4.7% and 6.7% respectively. The warfarin stable dosing algorithm acquired from the optimal regression model could explain 57.8% variation in warfarin dose. Conclusion This study suggested that genetic factors are the major determinants of the warfarin maintenance dose, and warfarin stable dosing algorithm may be useful for helping clinicians to prescribe warfarin with greater safety and efficiency.