背景 临床上氯吡格雷的治疗效果普遍存在个体差异,这与患者种族相关并受其基因型影响.目的 探讨急性冠脉综合征患者细胞色素P450的2C19(CYP2C19)基因多态性与氯吡格雷抗血小板作用及其预后之间的关系,以期为以基因分型为指导的个体化抗血小板治疗提供依据.方法 选取2012年3-12月在航天中心医院心脏中心住院治疗的急性冠脉综合征患者98例为研究对象.入院后给予患者氯吡格雷单次负荷剂量300 mg而后75 mg/d口服,或直接给予75 mg/d常规剂量口服.分别检测患者入院时、治疗3 d后血小板聚集率,血小板抑制率,氯吡格雷抵抗情况.采用Taqman-PCR技术检测患者CYP2C19基因型,根据CYP2C19基因检测结果,按照是否携带突变基因A将患者分为野生型组(第5外显子G681A位点和第4外显子G636A位点均无突变基因A,34例)和突变型组(第5外显子G681A位点或第4外显子G636A位点有突变基因A,64例).随访患者主要心血管不良事件(MACEs)发生情况.结果 CYP2C19*2基因型和CYP2C19*3基因型均符合Hardy-Weinberg平衡定律(P>0.05),提示本研究纳入的样本具有较好的群体代表性.不同CYP2C19*2基因型患者入院时血小板聚集率比较,差异无统计学意义(P>0.05).CYP2C19*2中,GA基因型患者治疗3 d后血小板聚集率大于GG基因型(P<0.05);CYP2C19*2中,AA基因型患者治疗3 d后血小板聚集率大于GG、GA基因型(P<0.05).CYP2C19*2中,GA、AA基因型患者血小板抑制率小于GG基因型(P<0.05).CYP2C19*2中,GG、GA基因型患者治疗3 d后血小板聚集率均小于入院时血小板聚集率(P<0.05).不同CYP2C19*3基因型患者入院时血小板聚集率、治疗3 d后血小板聚集率、血小板抑制率比较,差异无统计学意义(P>0.05).CYP2C19*3中,GG、GA基因型患者治疗3 d后血小板聚集率小于入院时血小板聚集率(P<0.05).野生型组患者氯吡格雷抵抗发生率小于突变型组(P<0.05).野生型组MACEs发生率小于突变型组(P<0.05).CYP2C19*2中,GG基因型患者MACEs发生率小于AA基因型(P<0.05);CYP2C19*2中,GA基因型患者MACEs发生率小于AA基因型(P<0.05).不同CYP2C19*3基因型患者MACEs发生率比较,差异无统计学意义(P>0.05).结论 急性冠脉综合征患者CYP2C19基因多态性与氯吡格雷抗血小板作用相关,含有CYP2C19第5外显子突变者服用常规剂量氯吡格雷后抗血小板作用减弱,预后较差,而第4外显子突变对患者预后影响相对较小.%Background There are general individual differences in the clinical efficacy of clopidogrel,which is related to race and affected by genotype.Objective To investigate the correlation of CYP2C19 genetic polymorphism with clopidogrel resistance and prognosis in patients with acute coronary syndrome(ACS) in order to provide a basis for individualized antiplatelet therapy guided by genotyping.Methods From March to December 2012,98 consecutive patients with ACS who were hospitalized at the Department of Cardiology of Aerospace Central Hospital were enrolled.After admission,patients were given clopidogrel at a first dose of 300 mg and then 75 mg/d orally,or administered directly at a regular dose of 75 mg/d.The platelet aggregation rate,platelet inhibition rate and clopidogrel resistance in all ACS patients were evaluated at the time of admission and after a clopidogrel therapy of 3 days.Meanwhile,CYP2C19 gene polymorphisms were determined by Taqman-PCR.Based on CYP2C19 gene test results,according to whether or not the mutant gene A was carried,patients were divided into wild-type group(without mutant gene A in both G681A in fifth exon and G636A in fourth exon,n=34) and mutant group(with mutant gene A in either G681A in fifth exon or G636A in fourth exon,n=64).Follow-up was applied,and major adverse cardiovascular events(MACEs) were recorded.Results The genotypes of CYP2C19*2 and CYP2C19*3 were in accordance with Hardy-Weinberg′s law of equilibrium(P>0.05),which suggested that the sample included in the study had a good population representativeness.There was no significant difference in baseline platelet aggregation rate between the patients with different CYP2C19*2 genotypes(P>0.05).In genotype CYP2C19*2 patients,clopidogrel resistance rate was significantly higher in GA patients than in GG patients after 3 days′ clopidogrel therapy(P<0.05),and clopidogrel resistance rate was significantly higher in AA patients than in GG and GA patients after 3 days′ clopidogrel therapy(P<0.05).In genotype CYP2C19*2 patients,GA and AA patients had lower platelet inhibition rate than GG patients(P<0.05).In CYP2C19*2 patients,the platelet aggregation rate in GG and GA genotype patients after clopidogrel therapy of 3 days was less than that at admission(P<0.05).There was no significant difference in platelet aggregation rate at admission,platelet aggregation rate after 3 days of treatment and platelet inhibition rate in different CYP2C19*3 genotype patients(P>0.05).In CYP2C19*3 genotype patients,the platelet aggregation rate in GG and GA genotype patients after clopidogrel therapy of 3 days was less than that at admission(P<0.05).Compared with mutant group,wild-type group had lower clopidogrel resistance(P<0.05);compared with mutant group,wild-type group had lower lower MACEs(P<0.05).In genotype CYP2C19*2 patients,GG patients had lower incidence of MACEs than AA patients(P<0.05),and GA patients had lower incidence of MACEs than AA patients(P<0.05).There was no significant difference in the incidence of MACEs in genotype CYP2C19*3 patients(P>0.05).Conclusion CYP2C19 gene polymorphism was associated with antiplatelet effects of clopidogrel in patients with ACS.Patients with CYP2C19 fifth exon mutation had reduced antiplatelet effects and poor prognosis after receiving conventional dose of clopidogrel,but the fourth exon mutation had relatively little effect on the prognosis of the patients.
展开▼
