【作者】 郭志强；

【导师】 贾正平；

【作者基本信息】 第四军医大学 ， 药理学， 2010， 博士

【摘要】 为确定细胞色素P450 2C19CYP2C19)在甘肃地区回族藏族汉族人群中的基因型及等位基因分布特征,并考察性别对其基因多态性的影响。本文通过选取甘肃地区回族藏族汉族无亲缘关系健康人,采用多聚酶链反应-限制性片段长度多态性(PCR-RFLP)法分析CYP2C19基因多态性。本研究中检测到CYP2C19的六个基因型,其分布在男女间无显著差异,但在三个民族间分布差异显著(P<0.05)。本研究表明在甘肃地区回族藏族汉族健康人群中,CYP2C19的基因型分布有显著差异,而性别对CYP2C19遗传多态性无显著影响。由于与细胞色素P450酶的相互作用,使用奥美拉唑会显著降低氯吡格雷抗血小板效力。因为大多PPIs由CYP2C19代谢,只是程度有所不同,我们假设已报道的负面奥美拉唑–氯吡格雷药物相互作用可能不是由类效应导致。在建立CYP2C19基因分型方法和甘肃地区主要聚居人口CYP2C19遗传多态性数据考察的基础上,本研究分别考察了CYP2C19遗传多态性对非ST段抬升急性冠脉综合症(NSTE ACS)患者冠脉支架植入术后合用2个质子泵抑制剂(PPIs) (奥美拉唑和泮托拉唑)的氯吡格雷抗血小板效应的影响。分别对行冠脉支架植入术后接受奥美拉唑或泮托拉唑20毫克治疗的241名和232名NSTE ACS患者进行前瞻性、随机研究。患者同时接受100毫克阿司匹林和75毫克氯吡格雷治疗。采用血小板反应活性指数(PRI)血管刺激磷蛋白(VASP)以测定氯吡格雷效应并以二磷酸腺苷(ADP)–诱导聚集指示血小板反应活性(ADP-Ag)。1个月后,以PRI VASP为指标,EMhomo组患者的血小板对氯吡格雷的反应显著好于PM组患者:36±20% vs50±17% (p=0.007)。与EMhomo组相比,在PM组中我们发现了更多的氯吡格雷无效者:44% vs 23% (p=0.04),优势比:2.6 (95%置信区间: 1.2 to 6.2)。相似地,以ADP-Ag为指标,EMhomo和PM组间血小板反应活性存在显著性差异:42.2±18%和62.7±15% (p=0.04)。结果提示,对于接受氯吡格雷治疗的患者而言,与奥美拉唑相比应优先使用泮托拉唑以避免任何潜在与CYP2C19相关的负面相互作用。更多还原

【Abstract】 We identify the genotype and allele distribution feature of cytochrome P450 2C19 (CYP2C19) in Chinese Hui,Zang and Han populations from Gansu area, and investigate the effects of gender on genetic polymorphism of CYP2C19 in these populations. The CYP2C19 genotypes of the unrelated healthy Chinese Hui,Zang and Han population subjects were assessed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Six different CYP2C19 genotypes were observed in this study. There was no significant difference between male and female, but significant difference among three Chinese populations (P<0.05). Population has significant effect on genetic polymorphism of CYP2C19 in Chinese Hui,Zang and Han populations from Gansu area, and gender hasn’t.Using of omeprazole to significantly decrease the clopidogrel antiplatelet effect because of cytochrome P450 interaction. Because all PPIs are metabolized by CYP2C19, but to a varying degree, we hypothesized that the reported negative omeprazole–clopidogrel drug interaction may not be caused by a class effect. On the bases of method for genotyping of CYP2C19 and the CYP2C19 polymorphisms of the major populations in Gansu area, this study sought to investigate the effect of the CYP2C19 polymorphisms on platelet response to clopidogrel with 2 proton pump inhibitors (PPIs) (omeprazole and pantoprazole) after coronary stenting for non–ST-segment elevation acute coronary syndrome (NSTE ACS). A total of 241 or 232 patients undergoing coronary stenting for NSTE ACS were prospectively included and taken omeprazole or pantoprazole 20 mg. They received at discharge 100-mg aspirin and 75-mg clopidogrel. Platelet reactivity index (PRI) vasoactive stimulated phosphoprotein (VASP) was used to assess clopidogrel response and adenosine diphosphate (ADP)–induced aggregation for platelet reactivity (ADP-Ag). After 1 month, patients belonging to EMhomo group had a significantly better platelet response to clopidogrel as assessed with the PRI VASP: 36±20%versus50±17% (p =0.007). We identified more clopidogrel nonresponders in the PM group than in the EMhomo group: 44%versus23%(p=0.04), odds ratio: 2.6 (95% confidence interval: 1.2 to 6.2). Similly, we observed significant difference in platelet reactivity with ADP-Ag between the EMhomo and PM groups:42.2±18% and 62.7±15%, respectively(p=0.04). The present findings suggest the preferential use of pantoprazole compared with omeprazole in patients receiving clopidogrel to avoid any potential negative interaction with CYP2C19.更多还原