基因多态性对华法林个体化药量作用的临床分析

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。

Effects of gene polymorphisms on individual warfarin dose

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.