VKORC1—1639G＞A、CYP2C93基因多态性及年龄、体质量对汉族肺血栓栓塞症患者华法林稳定剂量的影响

Influence of VKORCl-1639G〉A and CYP2C93 polymorphisms, age and body weight on warfarin stabledose in Han Chinese patients with pulmonary thromboembolism

目的探讨细胞色素P450酶2C9基因（CYP2C9）、维生素K环氧化物还原酶复合体亚单位1基因（VKORCl）多态性及非遗传因素对汉族肺血栓栓塞症患者华法林个体化用药的影响。方法连续纳入北京安贞医院185例确诊为肺血栓栓塞症服用华法林治疗的汉族患者，且PT-INR值范围在2．0～3．0，服药时间至少3个月。采用聚合酶链反应一限制性片段长度多态性（PCR-RFLP）技术检测VKORCl-1639G＞A和CYP2C93基因型，通过多元逐步回归分析得出华法林稳定剂量的预测公式。结果185例患者中，所需华法林稳定剂量差异较大，最小者为1．50mg／d,最大者为7．50mg／d。Spearman双变量秩相关分析显示：华法林稳定剂量与VKORCl-1639G〉A基因型（rs=0．482，P=0．000）、CYP2C9。3基因型（rs=0．244，P=0．001）及年龄（rs=0．409，P=0．000）显著相关；性别（P=0．153）、身高（P=0．526）、体质量（P=0.075）、体表面积（P=0．085）及平均INR值（P=0．135）与华法林稳定剂量相关不明显。采用多元逐步回归分析得出华法林稳定剂量方程：D=5．802-1．780×（VKORC1-1639AG）-3．395×（VKORC1-1639AA）-0．027×Age＋1.36×（CYP2C91／1）＋0．018×Weight。该方程可解释华法林稳定剂量个体差异总变异中的的51．7％。结论VKORC1-1639G〉A和CYP2C93基因多态性及年龄、体质量是引起汉族肺血栓栓塞症患者个体间华法林剂量差异的因素。

Objective To develope individualized warfarin dose, we investigated the impact of cytochrome P450 2C9 （CYP2C9） gene and vitamin K epoxide reductase complex subunit 1 （VKORCI） gene polymorphisms and non-genetic factors on warfarin dose in Han Chinese patients with pulmonary thromboembolism （PTE）. Methods We selected 185 patients from Beijing Anzhen Hospital with PTE who have been prescribed warfarin with a 2.0 3.0 range of prothrombin time normalized as an international normalized ratio for at least 3 months. VKORCl-1639G〉A and CYP2C93 were genotyped by the way of polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP）. We developed a warfarin stable dose predictive algorithm by multivariate stepwise regression analysis. Results There were great inter individual differences in warfarin stable dose in 185 patients, ranging from a minimum dose of 1.5 mg/d to a maximal dose of 7.5 mg/d. Spearman rank correlation analysis revealed that warfarin stable dose was significantly correlated with VKORCl-1639 genotype, CYP2C93 genotypeand age. There was no significant difference between warfarin stable dose and sex, height, weight, BSA and mean INR values. Stepwise multiple linear regression resulted in the following final algorithm of warfarin stable dose：D=5. 802-1. 780× （VKORCl-1639AG）-3. 395 ×（VKORCl-1639AA） -0. 027 × Age＋l. 36×（CYP2C91/1）＋0. 018 × Weight. The regression equation could account for 51.7% of overall inter-individual variation in warfarin stable dose. Conclusions VKORCl-1639G〉A and CYP2C93 gene polymorphisms, age and body weight were found to affect the inter-individual warfarin dosage variability in Han Chinese patients with PTE.