细胞色素P450 3A4 894C>T位点基因多态性与氯吡格雷抵抗的关系

Association between cytochrome P450 3A4 gene 894C>T single nucleotide polymorphism and clopidogrel resistance

目的探讨细胞色素P4503A4(简称CYP3A4)894C>T位点基因多态性与氯吡格雷抵抗(CR)发生的关系。方法采用病例-对照研究方法,共入选300例沈阳军区总医院心内科住院患者,根据血小板聚集率(PAR)分为病例组(CR组)和对照组(非CR组)。排除2周内曾服用氯吡格雷或噻氯匹啶者。患者入选后均给予氯吡格雷600mg和阿司匹林300mg负荷量治疗,并在服药前和服药后24h分别测定5μmol/L腺苷二磷酸诱导的PAR,根据两次测定结果计算PAR变化值,≤10%者定义为CR。所有患者均采集外周血提取基因组DNA,采用聚合酶链反应-限制性片段长度多态性技术(PCR-RFLP)检测患者CYP3A4基因894C>T单核苷酸多态性的基因型和等位基因分布。结果入选病例中共70例(23.3%)诊断为CR。CYP3A4894C>T位点在本组患者中存在多态性,分别为TT、CT和CC型,其基因型频率在CR组和非CR组分别为45.7%、50.0%、4.3%和63.5%、31.7%、4.8%。TT基因型的频率在非CR组明显高于CR组(OR=2.06,95%CI:1.201～3.547,P=0.020)。C等位基因型的频率在CR组明显高于非CR组,与T等位基因携带患者相比,C等位基因携带患者发生CR的危险性显著增加(OR=1.59,95%CI:1.037～2.442,P=0.023)。结论CYP3A4基因894C>T位点的多态性可能与CR的发生有相关性。

Objective To investigate the association between the single nucleotide polymorphism of cytochrome P450（CYP）3A4 894C〉T and the occurrence of clopidogrel resistance（CR）.Methods The present study is a case-control study.A total of 300 hospitalized patients in General Hospital of Shenyang Command were enrolled.All patients received loading doses of 600mg clopidogrel and 300mg aspirin.5μmol/L ADP-induced platelet aggregation ratio（PAR）was assessed before and 24h after clopidogrel administration.An absolute reduction of PAR≤10% compared with baseline was defined as CR.Genomic DNA was extracted from whole blood samples according to standard protocols,the single nucleotide polymorphism of the CYP3A4 894C〉T was genotyped by polymerase chain reaction-restriction fragment length polymorphism（PCR-RFLP）in all the patients.Results The occurrence of CR in this population was 23.3%（70/300）.There was CYP3A4 894C/T polymorphism in the study population.The frequencies of the three kinds of genotypes（CC,CT,TT）in CR group and non-CR（NCR）group were 45.7%,50.0%,4.3% and 63.5%,31.7%,4.8%,respectively.The frequency of TT genotype was significantly higher in NCR group than that in CR group（OR=2.06,95% CI：1.201-3.547,P=0.020）.C allele carriers were more likely to develop clopidogrel resistance compared with that of T allele carriers（OR=1.59,95% CI：1.037-2.442,P=0.023）.Conclusion CYP3A4 gene 894C/T polymorphism is associated with the risk of CR,and C allele carriers may be a possible genetic susceptibility factor for patients with CR.