昆明汉族人群VKORC1、CYP2C9基因多态性对华法林稳态剂量的影响及预测剂量模型的建立

摘要

目的 观察昆明地区汉族人群维生素K环氧化物还原酶复合体1(VKORC1)和细胞色素P4502C9(CYP2C9)基因多态性对华法林稳态剂量的影响,并建立预测剂量模型.方法 选择162例采取华法林抗凝治疗的下肢深静脉血栓患者,采用扩增阻滞突变体系-聚合酶链式反应技术(ARMS-PCR)检测患者血液中VKORC1、CYP2C9基因多态性;收集患者性别、年龄、身高、体质量、BMI、国际化标准比值(INR)、VKORC1和CYP2C9基因型,采用Pearson相关分析筛选与华法林稳态剂量相关的因素;综合华法林稳态剂量的相关因素进行多元逐步回归分析,得到预测剂量模型.另外选取20例下肢深静脉血栓患者,观察运用预测剂量模型推荐的华法林用量后出血性事件的发生情况.结果 162例患者中,CYP2C9 AA、AC基因型分别为151、11例,其中AC型华法林稳态剂量低于AA型;VKORC1的AA、AG、GG型分别为138、22、2例,其中AA型华法林稳态剂量低于AG型和GG型.患者年龄、体质量、VKORC1和CYP2C9基因多态性与华法林稳态剂量相关(P均<0.05).预测剂量模型:华法林用量=3.401-0.027×年龄+0.015×体质量-0.312×CYP2C9+0.979×(VKORC1-X1)+0.64×(VKORC1-X2).运用预测剂量模型推荐华法林用量的20例患者,在随访期间无出血事件发生.结论 昆明地区汉族人群存在 VKORC1和CYP2C9基因多态性,VKORC1和CYP2C9基因多态性对华法林稳态剂量具有一定的影响;成功构建了华法林预测剂量模型,该模型可较为准确地指导华法林用药.%Objective To study the effect of vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P4502C9 (CYP2C9) gene polymorphisms in Kunming Han population on steady-state dose of warfarin and to establish a predictive dose model. Methods Totally 162 blood samples from patients with deep venous thrombosis of lower extremity treated with warfarin anticoagulation were enrolled. The amplification block mutant system-polymerase chain reaction technology was used to detect the gene polymorphisms of VKORC1 and CYP2C9. The patients' age,sex,height,body weight, international standard ratio (INR) and the genotypes of VKORC1 and CYP2C9 were recorded. Pearson correlation analysis was used to screen the factors related to steady-state dose of warfarin. The multiple stepwise regression analysis of VKORC1 and CYP2C9 genotypes,age,sex,body weight,height,INR,and warfarin status in patients was used to predict the dose model. In addition,20 patients were selected to observe the occurrence of hemorrhagic events after using warfarin dosage recommended by the predicted dose model. Results During 162 cases of patients,there were 151 cases of CYP2C9 AA and 11 cases of CYP2C9 AC; among them,the warfarin recommended dose (combined amiodarone and non-amiodarone) of genotype AC was lower than that of genotype AA. The AA,AG,and GG types of VKORC1 were found in 138 cases,22 cases,and 2 cases,respectively; among them,the warfarin recommended dose (combined amiodarone and non-amiodarone) of AA type was significantly lower than that of the AG and GG types. The age,body weight,VKORC1,and CYP2C9 gene polymorphisms were related to the steady-dose of warfarin,but the height,BMI,and INR were not. The predictive dose model: Dose = 3.401 - 0.027 × Age + 0.015 × Weight - 0.312 × CYP2C9 + 0.979 × (VKORC1 - X1) + 0.64 ×(VKORC1 - X2),R2 = 0.816. Twenty patients using the predicted dose model did not have bleeding during the follow-up period. Conclusions There are VKORC1 and CYP2C9 gene polymorphisms in the Han population of Kunming. The gene polymorphisms of VKORC1 and CYP2C9 have a certain influence on steady-state dose of warfarin. We establish the warfarin predictive dose model and the established dose model can be used to accurately guide the medication of warfarin.