广州地区CYP2C19基因多态性及抗血小板药治疗下血管内皮相关因子水平研究

CYP2C19 gene polymorphisms and levels of factors related to vascular endothelial functions in Guangzhou Hans treated on anti-platelets

目的：调查广州地区汉族人群与氯吡格雷代谢相关的细胞色素P4502C19（CYP2C19）基因多态性分布特征，并探讨常规剂量氯吡格雷对不同CYP2C19基因型心脑血管患者血管内皮相关因子影响。方法选取本院行CYP2C19基因多态性检测的无亲缘关系的汉族人群1079例为研究对象，采用基因芯片法检测CYP2C19基因位点CYP2C19＊1、CYP2C19＊2、CYP2C19＊3，分析基因型频率和等位基因频率，并根据不同的等位基因分成快代谢型、中代谢型、慢代谢型。随机从快代谢型中选取患心脑血管疾病并且连续服用氯吡格雷（75 mg/d）抗血小板药超过6个月的患者28例为快代谢组，用同样的方法选取中代谢组26例、慢代谢组26例，慢代谢型中选取服用氯吡格雷（75 mg/d）＋阿司匹林（100 mg/d）联合用药患者13例为慢代谢联合用药组，选取患有心脑血管疾病没服用任何抗血小板药的患者27例作为对照组，检测各组患者血浆中血管内皮生长因子（VEGF）、血管细胞间黏附分子（VCAM-1）水平。结果广州地区汉族人群CYP2C19基因型以野生型为主，CYP2C19＊1＊1频率为41.97%， CYP2C19＊1＊2频率为39.85%，CYP2C19＊1＊3频率为5.65%，CYP2C19＊2＊2频率为9.08%，CYP2C19＊2＊3频率为3.05%，CYP2C19＊3＊3频率为0.58%，CYP2C19＊1、CYP2C19＊2和CYP2C19＊33种等位基因的发生频率分别为64.55%、30.53%和4.92%；CYP2C19代谢表型以中间代谢型为主（45.50%），其次是快代谢型（41.79%），慢代谢型（12.71%）最低。快、中、慢代谢组、对照组组间VEGF、VCAM-1水平比较有增高趋势，但差异无统计学意义（P〉0.05）。慢代谢氯吡格雷组与慢代谢联合用药组VEGF、VCAM-1水平比较，无统计学差异（P〉0.05）。结论广州地区汉族人群CYP2C19代谢表型以中间代谢型为主，其次是快代谢型，慢代谢型最低，服用常规剂量氯吡格雷联合阿司匹林对改善血管内皮相关因子并不优于单用氯吡格雷。

Objective To investigate the polymorphism of gene cytochrome P450 2C19 （CYP2C19）associated with clopidogrel metabolism in Guangzhou Han population,and to determine the effect of conventional clopidogrel doses on factors related to vascular endothelial functions in patients with cardio/cerebrovascular diseases and various CYP2C19 genotypes. Methods Included in this study were 1 079 unrelated Han subjects who received CYP2C19 polymorphism detection in our hospital. Gene microarray was used to detect the following CYP2C19 gene loci：CYP2C19＊1, CYP2C19＊2, and CYP2C19＊3. The frequencies of genotypes and alleles were analyzed. According to CYP2C19 alleles,the subjects were classified as rapid,intermediate or poor metabolizers. Twenty-eight rapid metabolizers who were suffering from cardio/cerebrovascular diseases and being treated on antiplatelet agent clopidogrel（75 mg/d）for over six consecutively months were randomly selected as the rapid metabolizer group. Likewise,intermediate（n=26）and poor metabolizer（n=26）groups were set. Another 13 poor metabolizers on combination therapy with clopidogrel （75 mg/d） plus aspirin （100 mg/d） were recruited as the combined treated poor metabolizer group. A control group was set comprising patients with cardio/cerebrovascular diseases but not on any antiplatelets （n=27）. For all groups,plasma levels of vascular endothelial growth factor （VEGF） and vascular cell adhesion molecule（VCAM-1）were determined. Results CYP2C19 genotypes in Guangzhou Han population were found predominated by wild-type. The frequencies were 41.97% for CYP2C19＊1＊1, 39.85%for CYP2C19＊1＊2,5.65%for CYP2C19＊1＊3,9.08%for CYP2C19＊2＊2,3.05%for CYP2C19＊2＊3,and 0.58%for CYP2C19＊3＊3. The allele frequencies of CYP2C19＊1,CYP2C19＊2 and CYP2C19＊3 were 64.55%,30.53% and 4.92%,respectively. CYP2C19 metabolizer phenotypes were chiefly intermediate metabolizers（45.50%）,followed by rapid metabolizers（41.79%）and poor metabolizers（12.71%）. The VEGF and VCAM-1 levels showed an increasing trend from rapid,intermediate,poor metabolizer groups to the control group,but the difference was not significant（P〉0.05）. Poor metabolizers on single clopidogrel therapy and those on combination therapy did not differ statistically in plasma VEGF and VCAM-1 levels（P〉0.05）. Conclusion In Guangzhou Han population,intermediate metabolizers account for most of CYP2C19 metabolizer phenotypes,followed by rapid metabolizers and poor metabolizers. Compared with Clopidogrel alone,conventional doses of clopidogrel in combination with aspirin do not lead to additional improvement in vascular endothelium-related factors.