对氯吡格雷不同反应的冠状动脉疾病患者基因型差异研究
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篇名: 对氯吡格雷不同反应的冠状动脉疾病患者基因型差异研究
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摘要: 目的:探讨对氯吡格雷不同反应的冠状动脉疾病(CAD)患者基因型的差异。方法:选取2013年3月-2015年11月于我院心内科就诊的CAD患者159例,予氯吡格雷+阿司匹林双联抗血小板治疗至少1年。采用光比浊法测定各患者治疗前后经腺苷二磷酸(ADP)、花生四烯酸(AA)诱导的血小板聚集百分率,采用聚合酶链反应-限制性片段长度多态性分析法检测其细胞色素P450(CYP)2C19、CYP3A5、野生型亮氨酸33等位基因(PLA1)/脯氨酸33等位基因(PLA2)的多态性。结果:共检出CYP2C19基因型3种(*2/*2、*2/*1、*1/*1)、CYP3A5基因型3种(*3/*3、*3/*1、*1/*1)、PLA1/PLA2基因型3种(A1/A2、A2/A2、A1/A1),各基因型频率均符合Hardy-Weinberg平衡(P>0.05)。159例患者中,有81例为氯吡格雷“半反应”,占50.9%;有78例为氯吡格雷“反应”,占49.1%。氯吡格雷“半反应”患者CYP2C19基因缺失(*2/*2或*2/*1基因型)和*2等位基因的频率均显著高于氯吡格雷“反应”患者,差异均有统计学意义(P<0.05);氯吡格雷“半反应”患者PLA1/PLA2基因缺失(A2/A2或A1/A2基因型)和A2等位基因的频率均显著高于氯吡格雷“反应”患者,差异均有统计学意义(P<0.05);而氯吡格雷“半反应”患者CYP3A5基因缺失(*3/*3或*3/*1基因型)和*3等位基因的频率虽略高于氯吡格雷“反应”患者,但差异均无统计学意义(P>0.05)。治疗后,各基因型患者经ADP、AA诱导的血小板聚集百分率均较治疗前显著降低,但CYP2C19基因缺失型、CYP3A5基因缺失型患者的血小板聚集百分率均显著高于其基因表达型(*1/*1基因型),差异均有统计学意义(P<0.05);PLA1/PLA2基因缺失型与其基因表达型(A1/A1基因型)患者的血小板聚集百分率比较,差异无统计学意义(P>0.05)。结论:氯吡格雷“半反应”在CAD患者中的发生率较高。CYP2C19、PLA1/PLA2基因多态性可能与氯吡格雷“半反应”有关,而CYP3A5基因多态性可能与之无关。CYP2C19、CYP3A5基因缺失可能会降低氯吡格雷对CAD患者血小板聚集的抑制作用。
ABSTRACT: OBJECTIVE: To explore the difference of genotypes in patients with coronary artery disease (CAD) and different responses to clopidogrel. METHODS: Totally 159 CAD patients were selected from cardiology department of our hospital during Mar. 2013-Nov. 2015. They were given clopidogrel+aspirin for dual antiplatelet therapy for at least 1 year. Turbidimetry method was used to detect the percentage of platelet aggregation induced by adenosine diphosphate (ADP) and arachidonic acid (AA) before and after treatment. The polymorphism of cytochrome P450 (CYP)2C19, CYP3A5, wild type leucine 33 allele (PLA1)/proline 33 allele (PLA2) were detected by PCR-RFLP. RESULTS: There were 3 kinds of CYP2C19 genotypes (*2/*2, *2/*1, *1/*1), 3 kinds of CYP3A5 genotypes (*3/*3, *3/*1, *1/*1) and 3 kinds of PLA1/PLA2 genotypes (A1/A2, A2/A2, A1/A1); the frequency of each genotype was in line with Hardy-Weinberg balance (P>0.05). Among 159 cases, there were 81 cases of clopidogrel “semi-response”, accounting for 50.9%; 78 cases of clopidogrel “response”, accounting for 49.1%. The frequencies of CYP2C19 gene deletion (*2/*2 or *2/*1 genotype) and *2 allele in clopidogrel “semi-response” patients were significantly higher than clopidogrel “response” patients, with statistical significance (P<0.05). The frequencies of PLA1/PLA2 gene deletion (A2/A2 or A1/A2 genotype) and A2 allele in clopidogrel “semi-response” patients were significantly higher than clopidogrel “response” patients, with statistical significance (P<0.05). The frequencies of CYP3A5 gene deletion (*3/*3 or *3/*1 genotype) and *3 allele in clopidogrel “semi-response” patients were slightly higher than clopidogrel “response” patients, without statistical significance (P>0.05). After treatment, the percentage of ADP or AA-induced platelet aggregation in different genotypes patients were significantly lowered, compared to before treatment; but the percentage of platelet aggregation in CYP2C19 gene deletion and CYP3A5 gene deletion patients were significantly higher than gene expression patients (*1/*1 genotype), with statistical significance (P<0.05). There was no statistical significance in the percentage of platelet aggregation between PLA1/PLA2 gene deletion patients and gene expression patients (P>0.05). CONCLUSIONS: The incidence of clopidogrel “semi-response” in CAD patients is high. CYP2C19 and PLA1/PLA2 gene polymorphism may be related to clopidogrel “semi-response”, while CYP3A5 gene polymorphism has no relationship with it. CYP2C19 and CYP3A5 gene deletion may weaken inhibitory effects of clopidogrel on platelet aggregation of CAD patients.
期刊: 2017年第28卷第11期
作者: 曾安宁,熊德高,石建,余吉西,陈荣兴,蔡冰冰
AUTHORS: ZENG Anning,XIONG Degao,SHI Jian,YU Jixi,CHEN Rongxing,CAI Bingbing
关键字: CYP2C19;CYP3A5;PLA1/PLA2;基因多态性;氯吡格雷;抵抗
KEYWORDS: CYP2C19; CYP3A5; PLA1/PLA2; Gene polymorphisms; Clopidogrel; Resistance
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