microRNA-605 rs2043556 polymorphisms affect clopidogrel therapy through modulation of CYP2B6 and P2RY12 in acute...

Clopidogrel therapy reduces the occurrence of major vascular events in acute coronary syndrome (ACS) patients, but treatment efficacy is variable. The present study aims to determine the mechanisms that underlie associations between certain miRNA polymorphisms and clinical outcomes of clopidogrel therapy. Our study focused on 9 miRNA single nucleotide polymorphisms in addition to CYP2C19*2 and CYP2C19*3. We found that the miR-605 rs2043556 AG genotype significantly decreased the risk of acute myocardial infarction (odds ratio, OR = 0.13, 95%CI 0.02-0.96, P = .045) and that the rs2043556 GG genotype significantly decreased the risk of unstable angina (OR = 0.19, 95%CI 0.05-0.65, P = .008) in ACS patients receiving clopidogrel therapy for more than one year. Dual-luciferase analysis indicated that miR-605 significantly decreased the mRNA expression of CYP2B6 and P2RY12 (P < .01). In cells treated with miR-605-A, the protein and mRNA expression of CYP2B6 and P2RY12 were significantly lower than that of cells treated with miR-605-G (P < .05). The results demonstrate that miR-605 targets the mRNA of the CYP2B6 and P2RY12 genes, and that rs2043556 A/G polymorphisms in miR-605 modulate the mRNA and protein expression of CYP2B6 and P2RY12 differently, which may impact the effect of clopidogrel in ACS patients.