Haplotype analyses of CYP2C19*2 and CYP2C19*17 genetic polymorphisms in clopidogrel non-responsiveness after percutaneous coronary intervention with stent implantation

Clopidogrel inhibits platelet activation and aggregation by blocking the P2Y12 receptor. Dual antiplatelet medication with aspirin and clopidogrel is currently recommended a strategy for patients undergoing percutaneous coronary intervention (PCI) with stent implantation. However, emerging non-responsiveness to clopidogrel often results in fatal stent thrombosis. Previous findings suggest that the CYP2C19*2 polymorphism is associated with non-responsiveness to clopidogrel and the CYP2C19*17 polymorphism enhances the antiplatelet activity of clopidogrel. We, therefore, aimed to analyze the haplotypes of these polymorphisms in clopidogrel non-responsiveness. Antiplatelet activity of clopidogrel was measured by the VerifyNow P2Y12 assay in blood samples collected from patients that took a standard dose of clopidogrel (75 mg/day) for at least 7 days. This assay containing fibrinogen-coated beads measures adenosine diphosphate-induced aggregation as an increase in light and reports the reactivity as P2Y12 reaction units (PRU). The cut-off of 208 PRU was used to assess responder and non-responder status. 243 responder and 104 non-responder patients underwent PCI with stent implantation are included in our study. The CYP2C19*2 (c.681G>A) and CYP2C19*17 (c.-806C>T) polymorphisms are genotyped using the Sequenom MassARRAY system. The genotype frequencies for each polymorphism were in good agreement with the predicted Hardy-Weinberg equilibrium values. Haplotype construction was analyzed using the SHEsis software which determines the most probable haplotypes based on allele frequencies. Haplotypes with a frequency of <0.03 were excluded. Only frequencies of the A-T haplotype were <0.03 in our study group. The comparison of the G-T haplotype frequencies between the responder and non-responder group did not reveal any significant difference. The A-C haplotype was significantly associated with non-responsiveness to clopidogrel (OR=2.855, 95%CI: 1.868-4.364, P<0.001). Conversely, the G-C haplotype was associated with responsiveness to clopidogrel (P=0.002). Our findings suggest that the A-C haplotype has a 2.8-fold increased risk and the G-C haplotype enhances the antiplatelet activity of clopidogrel. Checking the A-C and G-C haplotypes as a pharmacogenetics test for risk patients will make treatment effective. Thus, life-saving measures can be taken by specialists for the risk of lethal stent thrombosis or bleeding.