Decreased platelet responsiveness to clopidogrel correlates with CYP2C19 and PON1 polymorphisms in atherosclerotic patients

Clopidogrel and aspirin are the most commonly used medications worldwide for dual antiplatelet therapy after percutaneous coronary intervention. However, clopidogrel hyporesponsiveness related to gene polymorphisms is a concern. Populations with higher degrees of genetic admixture may have increased prevalence of clopidogrel hyporesponsiveness. To assess this, we genotyped CYP2C19, ABCB1, and PON1 in 187 patients who underwent percutaneous coronary intervention. Race was self-defined by patients. We also performed light transmission aggregometry with adenosine diphosphate (ADP) and arachidonic acid during dual antiplatelet therapy. We found a significant difference for presence of the CYP2C19*2 polymorphism between white and non-white patients. Although 7% of patients had platelet resistance to clopidogrel, this did not correlate with any of the tested genetic polymorphisms. We did not find platelet resistance to aspirin in this cohort. Multivariate analysis showed that patients with PON1 and CYP2C19 polymorphisms had higher light transmission after ADP aggregometry than patients with native alleles. There was no preponderance of any race in patients with higher light transmission aggregometry. In brief, PON1 and CYP2C19 polymorphisms were associated with lower clopidogrel responsiveness in this sample. Despite differences in CYP2C19 polymorphisms across white and non-white patients, genetic admixture by itself was not able to identify clopidogrel hyporesponsiveness.

氯吡格雷与阿司匹林是全球范围内经皮冠状动脉介入治疗后双联抗血小板治疗最常用的药物。然而，与基因多态性相关的氯吡格雷低反应性始终是临床关注的重点问题。遗传混合程度较高的人群，其氯吡格雷低反应性的患病率可能更高。为评估这一关联，研究团队对187名接受经皮冠状动脉介入治疗的患者进行了CYP2C19、ABCB1及PON1基因分型。患者自行申报所属种族。在双联抗血小板治疗期间，研究人员以腺苷二磷酸（adenosine diphosphate, ADP）与花生四烯酸为诱导剂，开展了光透射聚集试验检测。研究发现，白人与非白人患者之间，CYP2C19*2基因多态性的携带情况存在显著差异。尽管7%的患者存在血小板对氯吡格雷的抵抗现象，但该现象与本次检测的所有基因多态性均无相关性。本研究队列中未发现血小板对阿司匹林的抵抗现象。多因素分析结果显示，携带PON1与CYP2C19基因多态性的患者，其ADP诱导的血小板聚集试验后的光透射值显著高于携带野生型等位基因的患者。在光透射聚集试验结果偏高的患者中，未出现某一特定种族的占比优势。简言之，本研究样本中PON1与CYP2C19基因多态性与氯吡格雷反应性降低显著相关。尽管白人与非白人患者之间的CYP2C19基因多态性分布存在差异，但遗传混合本身无法有效识别氯吡格雷低反应性。