基因多态性对华法林个体化药量作用的临床分析

Effects of gene polymorphisms on individual warfarin dose

目的探讨细胞色素氧化酶P450(CYP2C9)和环氧化物还原酶复合体(VKORC1)基因型与华法林个体化剂量的关系。方法应用PCR-RFLP方法,检测临床长期口服华法林患者(362例)的VKORC1-1639及CYP2C9-1061A/C多态性,并按其基因型分组,分别比较VKORC1和CYP2C9不同基因型间的平均华法林剂量。结果病例检测出VKORC1-1639 AA基因型273例(75.4%)、AC基因型81例(22.3%)及CC基因型8例(2.3%)。CYP2C9基因检测AA型321例(88.7%)、AG基因型34例(9.5%)、GG型7例(1.8%)。两组VKORC1和CYP2C9各基因型分布差异无统计学意义(P>0.05)。VKORC1不同基因型间患者所需华法林平均剂量GA、GG组明显高于AA组(P<0.01)。携带CYP2C9基因型的患者(AG+GG)组华法林平均剂量要低于AA组(P<0.05)。结论华法林应用剂量偏低可能与VKORC G-C和CYP2C9 A-G转变有关。VKORC1 AA型占多数可能是中国汉族人群所需华法林剂量普遍较低的重要原因。

Objective To investigate the quantitative influence of cytochrome P4502C9（CYP2C9）and epoxide reductase complex subunit 1（VKORC1）polymorphisms on warfarin dose requirements.Methods 362 patients taking warfarin were enrolled in the study.PCR-RFLP technique was used to genotype the CYP2C9-1061A/C and VKORC1-1639 polymorphism in warfarin-treated patients.The mean warfarin doses used for the patients with different VKORC1 and CYP2C9 genotypes were compared.Results The frequencies of the VKORC1-1639 AA,AG,GG genotypes of patients were 75.4%,22.3% and 2.3% respectively;frequencies of the CYP2C9-1061 AA,AC,CC genotypes of patients were 88.7%,9.5% and 1.8% respectively.There was no significant difference in genotype distribution of VKORC1-1639 and CYP2C9-1061 between the patients and the healthy controls（P0.05）.The mean warfarin dose differed significantly among the VKORC1 genotypes（P0.001）;the patients carrying VKORC1-1639 AA genotypes had a lower mean warfarin dose than those carrying AG genogype（P0.05）,and the mean warfarin dose of the patients with AG genotype was lower than those with GG genotype（P0.05）.The carriers of CYP2C9-1061 C allel（AC＋CC）had a lower warfarin dose than those with CYP2C9-1061 AA genotype（P0.05）.Conclusion There might be an association between VKORC1-1639 G-A,CYP2C9-1061 A-C transformation and decreased warfarin dose,and the major genotype of VKORC1-1639（AA）might be the reason for the universally lower warfarin dosage used in Chinese Han population.