CYP2C19基因多态性指导下的个体化抗血小板治疗

发布时间：2018-01-07 22:20

本文关键词：CYP2C19基因多态性指导下的个体化抗血小板治疗　出处：《河北医科大学》2015年硕士论文　论文类型：学位论文

【摘要】：目的:氯吡格雷抵抗(Clopidogrel resistance,CR)增加冠脉支架植入术后不良心血管事件的发生,而CR又与CYP2C19基因多态性有关,但是根据基因多态性及早调整经皮冠状动脉介入(Percutaneous coronary interention,PCI)术后抗血小板治疗能否降低心血管不良事件并不明确。本研究旨在探讨根据CYP2C19基因多态性个体化指导PCI术后抗血小板治疗对不良心血管事件的影响,从而为临床治疗提供更多的循证医学证据。方法:连续入选2013年4月至2014年1月因急性冠脉综合征(Acute coronary syndrome,ACS)就诊北京军区总医院并成功完成PCI手术的汉族患者338例,所有患者以1:2比例随机分入常规治疗组(Routine treatment group,RTG)和个体化治疗组(Individualized treatment group,ITG)。RTG组于支架植入术后口服阿司匹林75~100mg/日+氯吡格雷75mg/日,同时进行CYP2C19基因检测,但不根据结果调整药物。ITG组则根据是否携带CYP2C19功能缺失(Loss-of-function,LOF)等位基因分为LOF+、LOF-2个亚组,LOF+组为携带LOF等位基因(CYP2C19*2或*3任一多态性位点的GA和AA)组,支架植入术后给予阿司匹林75~100mg/日+替格瑞洛90mg 2/日;LOF-组为不携带LOF等位基因组,支架植入术后给予阿司匹林75~100mg/日+氯吡格雷75mg/日。比较组间患者9~12个月内主要不良心血管事件(Major adverse cardiovascular events,MACE)、支架内血栓、再发心绞痛及出血事件(主要出血、小出血、轻微出血)的发生率。MACE包括心源性死亡、非致死性心梗、卒中及靶血管再次血运重建。结果:本研究最终纳入患者301例,其中RTG组98例,ITG组203例。37例被剔除(5例患者要求终止实验,23例失访,9例患者终止双联抗血小板药物)。1 RTG组与ITG组临床资料及手术资料的比较年龄、性别、ACS类型(UA、Non-STEMI、STEMI)、冠心病危险因素(吸烟、糖尿病、高血压病、高脂血症)、合并用药(他汀类、β受体阻滞剂、ACEI或ARB)及辅助检查(空腹血糖、血尿酸、肌酐、总胆固醇、甘油三酯、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、血红蛋白)等临床资料在两组间的差异无统计学意义(P均0.05)。除右冠脉受累患者数量外(62.2%vs46.3%,P0.05),两组患者病变在前降支、回旋支、左主干及单支、双支、多支病变、支架植入数目等方面差异均无统计学意义(P均0.05)。2 CYP2C19基因型检测结果及两组分布的比较2.1 CYP2C19*2和CYP2C19*3单核苷酸多态位点基因型分布符合Hardy-Weinberg平衡定律。2.2 CYP2C19*2单核苷酸多态位点存在突变纯合子(AA)、突变杂合子(GA)、野生型(GG)三种基因型,在RTG和ITG两组之间的分布差异无统计学意义(P0.05);CYP2C19*3单核苷酸多态位点存在突变杂合子(GA)、野生型(GG)两种基因型,在两组之间的分布差异也无统计学意义(P0.05)。对所有入组患者进行分析,CYP2C19*2 A等位基因频率为32.2%;CYP2C19*3 A等位基因频率为4.0%。3观察终点的比较观察时间9~12个月,RTG和ITG两组患者疗效终点(MACE、支架内血栓、再发心绞痛)及安全终点(主要出血、小出血、轻微出血)均无明显差异(P均0.05)3.1对RTG组患者进行回顾性分析,携带CYP2C19 LOF等位基因患者终点事件(疗效终点)的发生率高于不携带者,但两组差异无统计学意义(P均0.05)。3.2对所有携带CYP2C19 LOF等位基因患者进行回顾性分析,替格瑞洛组终点事件(疗效终点)的发生率低于氯吡格雷组,但两组无明显差别(P均0.05)。4替格瑞洛其他副作用观察15.3%的患者发生轻中度呼吸困难,2.4%的患者发生缓慢性心律失常,但患者均能耐受,不需调整替格瑞洛的治疗。5 CYP2C19基因型与血栓弹力图的比较携带LOF等位基因的患者中,血栓弹力图提示CR的几率为49.7%,不携带LOF等位基因的患者中,血栓弹力图提示CR的几率为46.0%,未发现CYP2C19基因型与血栓弹力图提示CR存在相关关系(P0.05)。结论:基于CYP2C19基因多态性的个体化抗血小板治疗未能明显降低终点事件的发生,但仍需要大规模研究进一步证实。携带CYP2C19 LOF等位基因患者终点事件(疗效终点)的发生率高于不携带者,对携带LOF等位基因患者给予替格瑞洛治疗后终点事件(疗效终点)发生率低于氯吡格雷,但均未观察到明显差别,仍需进一步大规模研究观察。CYP2C19基因型与血栓弹力图提示CR不存在相关关系,根据基因型预测血栓弹力图CR结果并无意义。
[Abstract]:Objective: clopidogrel resistance (Clopidogrel resistance, CR) increased after coronary stent implantation and the incidence of adverse cardiovascular events associated with CR and CYP2C19 gene polymorphisms, but according to the gene polymorphism to adjust early percutaneous coronary intervention (Percutaneous coronary, interention, PCI) postoperative antiplatelet therapy can reduce the adverse cardiovascular events is not clear. The research aimed to investigate the polymorphism of CYP2C19 gene according to the individual guidance after PCI antiplatelet therapy effect on adverse cardiovascular events, so as to provide more evidence for clinical treatment. Methods: a total of April 2013 to January 2014 due to acute coronary syndrome (Acute coronary, syndrome, ACS) of 338 Han patients in General Hospital of Beijing Military Region and the successful completion of PCI operation the patients, all patients with a ratio of 1:2 were randomly divided into routine treatment group (Routine treatment, grou P, RTG) and individual treatment group (Individualized treatment, group, ITG) in the.RTG group after stent implantation in oral aspirin 75~100mg/ and clopidogrel 75mg/, and CYP2C19 gene was detected, but not according to the results of adjustment of drug.ITG group according to whether they carry the loss of function of CYP2C19 (Loss-of-function, LOF) alleles for LOF+ LOF-2, a sub group, LOF+ group for the LOF allele (CYP2C19*2 or *3 any polymorphic loci GA and AA) group, after stent implantation with aspirin 75~100mg/ + ticagrelor 90mg 2/; group LOF- was not carrying the LOF allele, after stent implantation on 75~100mg/ + aspirin clopidogrel 75mg/. Compared with 9~12 months of major adverse cardiovascular events (Major adverse cardiovascular events, MACE), stent thrombosis, recurrent angina and bleeding events (major bleeding, minor bleeding, light Micro hemorrhage) the incidence of.MACE including cardiac death, non fatal myocardial infarction, stroke and target vessel revascularization. Results: the study included 301 patients, including 98 cases of RTG group, ITG group of 203 cases of.37 patients were excluded (5 cases for the termination of the experiment, 23 cases were lost, 9 patients terminated dual antiplatelet drugs) age,.1 RTG group and ITG group, the clinical data and surgical data of gender, type ACS (UA, Non-STEMI, STEMI), coronary heart disease risk factors (smoking, diabetes, hypertension, hyperlipidemia), combined drugs (statins, beta blockers, ACEI or ARB) and auxiliary examination (fasting blood glucose, blood uric acid, creatinine, total cholesterol, triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol, hemoglobin) there was no significant difference between the two groups in the clinical data (P 0.05). In addition to the number of right coronary artery involvement in patients with (62.2%vs46.3%, P0.05) , two groups of patients with lesions in the anterior descending and circumflex, left main and single, double and multi vessel lesions, stent implantation and other aspects of the number of differences were not statistically significant (P 0.05) distribution of test results of.2 CYP2C19 genotype and two groups compared with the distribution of 2.1 CYP2C19*2 and CYP2C19*3 SNP genotypes with.2.2 CYP2C19*2 Hardy-Weinberg equilibrium SNP mutation (AA), homozygous mutation heterozygote (GA), wild type (GG) three genotypes, no statistically significant differences in the distribution of RTG and ITG between the two groups (P0.05); CYP2C19*3 SNP mutation heterozygous (GA), wild type (GG) two genotypes, the difference in distribution between the two groups has no statistical significance (P0.05). All of the patients were analyzed, the CYP2C19*2 A allele frequency was 32.2% CYP2C19*3; the A allele frequency was observed than the end point 4.0%.3 The observation time was 9~12 months, end point RTG and ITG two groups of patients (MACE, stent thrombosis, recurrent angina) and safety end point (major bleeding, minor bleeding, minor bleeding) were not significantly different (P 0.05) of 3.1 RTG patients were retrospectively analyzed with CYP2C19 LOF and other end point an event (efficacy end point) gene in patients with a higher incidence of non carriers, but there was no significant difference between the two groups (P 0.05).3.2 on all CYP2C19 carrying LOF allele were retrospectively analyzed, ticagrelor group end point events (efficacy end point) the occurrence rate is lower than that of clopidogrel group, but the two group significant difference (P 0.05).4 for Grillo and other side effects were observed in 15.3% patients with mild to moderate dyspnea, 2.4% patients with slow arrhythmia, but were tolerated, no adjustment is required for the treatment of.5 CYP2C19 genotype and Thrombelastogram Grenada than Los Compared with the patients carrying LOF allele, probability of Thrombelastogram indicated that CR was 49.7%, not carrying the LOF allele in patients with risk of Thrombelastogram indicated that CR was 46%, CYP2C19 was not found in genotype and Thrombelastogram indicated CR correlation (P0.05). Conclusion: individualized antiplatelet therapy not CYP2C19 gene polymorphism significantly lower end point events based on, but still needs further large-scale studies confirmed. Carrying the CYP2C19 LOF gene in patients with end point (efficacy end point) was higher than that in non carriers, given end point events ticagrelor after treatment of patients with LOF allele (efficacy end point) and lower incidence clopidogrel, but there was no obvious difference, still need further observation of large-scale study of.CYP2C19 genotypes and Thrombelastogram indicated that CR is not related, according to genotype thrombelastometry prediction Figure CR results are meaningless.

【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R541.4

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