肝细胞色素P450系统基因多态性对下肢动脉硬化闭塞症支架术后患者服用氯吡格雷的远期疗效影响  

Association between CYP2C19 genotype and the clinical efficacy of clopidogrel therapy in Chinese patients with arteriosclerosis obliterans after stent implantation

作　　者：赵瀛[1] 周琰[1] 张岚[1] 鞠颖慧 张春燕 郭玮[1] 潘柏申[1] 郭大乔[2] 

机构地区：[1]复旦大学附属中山医院检验科,上海200032 [2]复旦大学附属中山医院血管外科,上海200032

出　　处：《中华临床实验室管理电子杂志》2015年第4期225-229,共5页Chinese Journal of Clinical Laboratory Management(Electronic Edition）

基　　金：国家自然科学基金资助项目(81572064);上海市卫生计生系统重要薄弱学科建设项目(2015ZB0201)

摘　　要：目的探讨肝细胞色素P450系统CYP2C19基因多态性在下肢动脉硬化闭塞症(atherosclerosis obliterans,ASO)患者中的分布规律,及其与氯吡格雷治疗下肢ASO支架术后患者远期疗效的相关性。方法选取2011年1月至2012年12月在复旦大学附属中山医院血管外科行支架植入手术的下肢ASO患者50例,按泛大西洋学会联盟(Trans-Atlantic Inter-Society Consensus,TASC)II分级A^C,采用测序法检测影响氯吡格雷代谢活性基因(CYP2C19*2,*3,*17)的单核苷酸多态性分布。采用多普勒超声和周围血管检查随访12个月,对疑难病例用X光、CT血管造影共同评价患者支架内狭窄程度,以分析年龄、身体质量指数、性别、糖尿病、高血压、脑梗、冠心病、吸烟史等因素对支架术后患者临床预后的影响。结果 50例下肢ASO支架术后患者中,CYP2C19*2、*3等位基因突变频率分别为48.0%(24/50)、6.0%(3/50)。CYP2C19快代谢型(*1/*1)、中代谢型(*1/*2、*1/*3)、慢代谢型(*2/*2、*2/*3)的比例分别为48.0%(24例)、44.0%(22例)、8.0%(4例)。50例下肢ASO支架术后服用氯吡格雷患者经12个月随访,CYP2C19代谢型和吸烟史所预示终点事件发生的风险比(Hazard ratio,HR)分别为2.688,95%CI 1.366~5.288,P=0.004;HR 2.430,95%CI 1.024~5.765,P=0.044。经Kaplan-Meier生存分析,12个月中携带1个丧失功能型(loss-of-function,LOF)、2个LOF、不携带LOF等位基因的下肢ASO患者间发生缺血性事件的差异有统计学意义(P=0.007)。但CYP2C19*2和*3对下肢ASO患者缺血性事件影响的差异无统计学意义(P=0.05)。结论 CYP2C19基因多态性对服用氯吡格雷治疗下肢ASO患者远期疗效有影响,携带LOF等位基因可能增加缺血事件发生的风险。但由于本研究病例数少,需扩大样本量予以进一步验证。Objective To figure out the regularities of distribution of cytochrome P450-2C19（CYP2C19） in atherosclerosis obliterans（ASO） patients with arteriosclerosis obliterans after stent implantation, and to define the association between the CYP2C19 genotype and the risk of long-term ischemic events in those who receiving clopidogrel. Methods A total of 50 selectived patients with ASO after stent implantation（TASC A^C） were included from January 2011 to December 2012. It was used to assess the relation of single nucleotide polymorphisms within genes modulating clopidogrel metabolic activation（CYP2C19＊2, ＊3, ＊17）using chain termination DNA sequencing method. Doppler ultrasound was used to screen follow-up of 12 months. For difficult cases, CTA and DSA were both used to evaluation of patients with common stent stenosis, which was in order to andlyze age, body mass indeoc, gender, diabetes, hypertension, cerebral infarction, factors of coronary heart disease, smoking history of stent clinical prognosis. Results The allelic mutation frequencies of CYP2C19＊2 and ＊3 were 48.0%（24/50） and 6.0%（3/50）. The frequencies of extensive metaboliers, intermediate metabolizers and poor metabolizers were 48.0（n=24）, 44.0%（n=22） and 8.0%（n=4）, respectively. Among 50 patients, CYP2C19 genotypes（HR 2.688, 95% CI 1.366-5.288, P=0.004） and smoking（HR 2.430, 95% CI 1.024-5.765, P=0.044） were significant predictors of the primary endpoint. In Kaplan-Meier analysis with the CYP2C19 loss-of-function（LOF） genotype, the CYP2C19 LOF carrier status was associated with an increased rate of ischemic events（P=0.007）, compared with non-carriers during a year＇s follow-up. However, the effect of the CYP2C19＊2 versus the ＊3 allele on ischemic events did not differ（P0.05）. Conclusion Among ASO patients treated with clopidogrel after stent implantation, CYPRC19 LOF allele carries have a higher risk of ischemic events, particularly stent thrombosis, than non-noncarriers.

关 键 词：肝细胞色素P450系统 单核苷酸多态性 氯吡格雷 下肢动脉硬化闭塞症 

分 类 号：R543.5[医药卫生—心血管疾病] R440[医药卫生—内科学]