Interaction of CYP2C19, P2Y12, and GPIIIa Variants Associates with Efficacy of Clopidogrel and Adverse Events on Patients with Ischemic Stroke

Abstract

Objective: Clopidogrel is a clinically important oral antiplatelet agent for the treatment or prevention of cerebrovascular disease. However, different individuals have different sensitivities to clopidogrel. This study assessed variants of different genes for association with response to clopidogrel, clinical outcome, and side effects in patients with ischemic stroke (IS). Methods: We consecutively enrolled 375 patients with IS after they received clopidogrel therapy, and venous blood samples were subjected to genotyping allelic variants of genes modulating clopidogrel absorption (ATP binding cassette subfamily B1, ABCB1), metabolic activation (cytochrome P450[CYP] 3A and CYP2C19), and biologic activity (platelet membrane receptor [P2Y12, P2Y1)], and glycoprotein IIIa [GPIIIa]) and statistically analyzing their interactions with clopidogrel sensitivity (CS) and adverse events, risk of IS recurrence, myocardial infarction, and death during 6 months of follow-up. Results: Adverse events occurred in 37 patients (31 had IS recurrence, 4 died, and 2 had myocardial infarction) during the first 6 months of follow-up. Single locus analysis showed that only the CYP2C19∗2(rs4244285) variant was independently associated with CS and risk of adverse events after adjusting covariates. However, there was significant gene-gene interaction among CYP2C19∗2(rs4244285), P2Y12(rs16863323), and GPIIIa (rs2317676) analyzed by generalized multifactor dimensionality reduction methods. The rate of adverse events among patients with the 3-loci interaction was 2.82 times the rate among those with no interaction (95% confidence interval: 2.04-8.63). Conclusion: Sensitivity of patients with IS to clopidogrel and clopidogrel-induced adverse clinical events may be multifactorial but is not determined by single gene polymorphisms.