【作者】 杨慧；

【导师】 吴贵恺；

【作者基本信息】 河北医科大学 ， 内科学， 2016， 硕士

【摘要】 目的:本研究拟探讨细胞色素P450 2C19(CYP2C19)*2、CYP2C19*3基因多态性与药物洗脱支架植入术后接受阿司匹林与氯吡格雷双联抗血小板的冠心病(coronary heart disease,CHD)患者的消化道出血的发生是否具有相关性,有何相关性。分析CYP2C19*2、*3突变与氯吡格雷代谢的关系,并探索接受双联抗血小板患者出现消化道出血的危险因素,以指导经皮冠状动脉介入术(Percutaneous coronary interventions,PCI)植入药物洗脱支架后抗血小板药物的应用,减少术后接受双联抗血小板患者消化道出血的发生。方法:收集2014年9月1日至2015年2月1日收入唐山工人医院心内科接受PCI术植入药物洗脱支架患者的一般临床资料,包括性别、年龄、血压、血胆固醇、吸烟情况及有无糖尿病、消化性溃疡病史、消化道出血病史、是否有幽门螺杆菌(Helicobacter pylori,Hp)感染、他汀类药物使用与否等情况。术后所有患者依据PCI术后相关指南应用阿司匹林与氯吡格雷双联抗血小板(Dual antiplatelet therapy,DATP)治疗。采集其静脉血,应用CYP2C19基因检测试剂盒(DNA微阵列芯片法)检测患者CYP2C19基因*1、*2、*3多态性。根据基因型的不同,将患者分为快代谢型(Extensive metabolizer)组,即EM组,基因型为CYP2C19*1/*1;中间代谢型(Intermediate metabolizer)组,即IM组,基因型为CYP2C19*1/*2、CYP2C19*1/*3;慢代谢型(Poor metabolizer)组,即PM组,基因型为CYP2C19*2/*2、CYP2C19*3/*3、CYP2C19*2/*3。3月后应用血栓弹力图检测每位患者的ADP、AA诱导的血小板抑制率。通过再入院记录、电话随访、门诊每月复查血常规及便常规对入选患者进行跟踪随访12个月,了解和诊断患者是否发生了消化道出血事件。结果:1共532例患者纳入研究随访,因外科手术提前终止氯吡格雷治疗6例,因心血管事件、脑血管疾病死亡5例,其他原因停服氯吡格雷4例,失访13例。最终进入统计分析患者504例,其平均年龄(62.19±7.22)岁。男性340例,占67.5%;女性164例,占32.5%,男女比例为2.07:1。2根据基因型分布,504例患者分为快代谢型组(EM)257例(51.0%);中间代谢型组(IM)216例(42.9%);慢代谢型组(PM)31例(6.2%)。三组患者的年龄、性别、既往吸烟史、糖尿病、高血压、高脂血症病史等一般临床资料无统计学差异(P>0.05);三组患者消化道出血危险因素(消化性溃疡病史、消化道出血病史、Hp感染阳性)也无统计学差异(P>0.05);三组患者他汀类药物使用情况无统计学差异(P>0.05);三组患者AA诱导的血小板抑制率无统计学差异(P>0.05)。3在504例患者中,基因型为CYP2C19*1/*1的患者257例,占51.0%;基因型为CYP2C19*1/*2患者167例,占33.1%;基因型为CYP2C19*1/*3患49例,占10.0%;基因型为CYP2C19*2/*2患者23例,占4.6%;基因型为CYP2C19*2/*3患者5例,占1.0%,基因型为CYP2C19*3/*3患者3例,占0.6%。基因频率:CYP2C19*1的频率为72.7%,CYP2C19*2的频率为21.7%,CYP2C19*3的频率为6.0%,符合Hardy-Weinberg遗传检测平衡(见表5)。说明样本来自一个处于随机婚配的平衡状态的大群体,本样本的选取具有一定代表性。4 EM组患者ADP诱导的血小板抑制率为(56.2±5.3)%,IM组患者ADP诱导的血小板抑制率为(47.2±9.0)%,PM组患者ADP诱导的血小板抑制率为(44.6±9.2)%。三组血小板抑制率具有显著的统计学差异(P<0.01)。5 1年随访发现EM组患者中有32例患者发生消化道出血,占同组12.5%;IM组患者中有13例患者发生消化道出血,占同组6.02%;PM患者组中有2例患者发生消化道出血,占同组6.45%。三组消化道出血发生率具有统计学差异(P<0.05),且EM组消化道出血发生率显著高于其他两组。6根据多因素非条件logistic回归分析,得出以消化道出血作为因变量,年龄、吸烟史、代谢型、既往消化性溃疡病史、既往消化道出血史、Hp感染情况作为自变量分析消化道出血的危险因素,结果入选主效应模型的变量有年龄、吸烟史、代谢型、既往消化道出血史、消化道溃疡病史、Hp感染。结论:1对于PCI术后的CHD患者,CYP2C19基因多态性影响氯吡格雷的药效,携带CYP2C19*2和CYP2C19*3等位基因的患者应用氯吡格雷后ADP诱导的血小板抑制率低于非突变基因型患者。2 PCI术后服用阿司匹林和氯吡格雷的冠心病患者,消化道出血的发生与CYP2C19基因多态性有关,携带CYP2C19*2和CYP2C19*3等位基因的患者消化道出血事件发生率低于非突变基因型患者。3 PCI术后服用阿司匹林和氯吡格雷的冠心病患者,消化道出血的发生与年龄、吸烟史、代谢型、既往消化道出血史、消化道溃疡病史、Hp感染相关,而与性别、高血压、高血脂、糖尿病并无明显关系。更多还原

【Abstract】 Objective:To research correlation between Cytochrome P450 2C19 gene polymorphism and risk of gastrointestinal bleeding of coronary heart disease patients on dual antiplatelet therapy after percutaneous coronary intervention(PCI),and to explore the influence of CYP2C19*2,CYP2C19*3 mutation on clopidogrel metabolism,and to explore the risk factors for gastrointestinal bleeding in patients accepting dual antiplatelet therapy.Which were helpful to guide the use of antiplatelet drugs,reduce gastrointestinal bleeding.Methods: A total of 532 patients underwent successful coronary stenting and involved clopidogrel and aspirin standardly were included.Those patients’ general clinical datas,such as including age,gender,blood pressue,blood fat,smoking,diabetes,peptic ulcer,earlier history of GIB,history of h.pylori infection,statin using were recorded.CYP2C19*1,CYP2C19*2 and CYP2C19*3 genotyping were performed.All patients were divided into three groups according to their metabolic type: Extensive metabolizer,Intermediate metabolizer and Poor metabolizer.Platelet inhibition ratio was measured by thromboelasto graphy 3 months later.During the 12-month follow-up period,the author recorded those patients’ records of reentry,telephone,or monthly fecal occult blood tests,month-ly routine blood tests.Results: Of 532 patients were involved in the study,504 finish the study.The average age was(62.19±7.22).There were 340(67.5%)males and 164(32.5%)females.According to CYP2C19 genotype,patients were divided into 3 groups: Extensive metabolizers(EM),including 257 patients,account for 51.0%;Intermediary metabolizers(IM),including 216 patients,account for 42.9%;and Poor metabolizers(PM),including 31 patients,account for 6.2%.No differences were found in age,gender,smoking,diabetes,hypertension or hyperlipidemia among these 3 proups.At the same time,no differences are observed in risk factors of GIB(peptic ulcer,earlier history of GIB,history of h.pylori infection);no differences are observed in using of statins;no differences were found in platelet aggregation inhibition rate by AA.Among the patients included this study,257 patients with the genotype of CYP2C19*1/*1,accounting for 51.0%;167 patients with the genotype of CYP2C19*1/*2,accounting for 33.1%;49 patients with the genotype of CYP2C19*1/*3,accounting for 10.0%;23 patients with the genotype of CYP2C19*2/*2,accounting for 33.1%;5 patients with the genotype of CYP2C19*2/*3,accounting for 1.0%;3 patients with the genotype of CYP2C19*3/*3,accounting for 0.6%.The frequency of CYP2C19*1 was 72.7%,CYP2C19*2 was 21.7%,CYP2C19*3 is 6.0%.Distribution of CYP2C19 genotype was in conformity with Hardy Weinberg equilibrium,which means those patients come from a large and random mating population.Platelet aggregation inhibition rate by ADP in Extensive metabolizers is 56.2±5.3%,intermediate metabolizers’ is 47.2±9.0%,poor metabolizers’ is 44.6±9.2%.Platelet aggregation inhibition rate by ADP is significantly different among these three groups.During the follow-up periods,32 patients in EM encountered gastrointestinal hemorrhage,accounting for 12.5%,and 13 patients in IM encountered gastrointestinal hemorrhage,accounting for 6.02%,ang 2 patients in PM encountered gastrointestinal hemorrhage,accounting for 6.45%.The rates of gastrointestinal bleeding in three groups are statistically difference(P < 0.05),and the incidence of gastrointestinal bleeding in EM is obviously higher than other two groups.Using Logistic regression model to analyze the related factors influencing the happen of gastrointestinal hemorrhage,it was found the following facts significantly increased risk of gastrointestinal hemorrhage: age,smoking,metabolic type,history of gastrointestinal bleeding,history of peptic ulcer and infection of helicobacter pylori.Conclusions:1 In patients with coronary artery disease,who underwent PCI,CYP2C19 gene polymorphisms affect the efficacy of clopidogrel antiplatelet,the platelet aggregation inhibition rates of ADP with CYP2C19*2 and CYP2C19* 3 allele were lower than the non-mutation genotype.2 For patients with coronary heart disease,CYP2C19 gene polymorphisms is associated with the occurrence of gastrointestinal bleeding,gastrointestinal bleeding events with CYP2C19*2 and CYP2C19*3 allele were more than non-mutation genotype.3 For patients with coronary heart disease,accepted aspirin and clopidogrel dual antiplatelet therapy after PCI,the emergence of gastrointestinal bleeding correlates with age,smoking,metabolic type,history of gastrointestinal bleeding,history of peptic ulcer and infection of helicobacter pylori,and no correlate with gender,hypertension,history of diabetes,hyperlipidemia.更多还原