Association of polymorphic variants of CYP2C19, P2RY12, ITGB3, ITGA2 and eNOS3 genes with high residual platelet reactivity while taking clopidogrel and acetylsalicylic acid at different terms of myocardial infarction

Abstract

Aim. Study of the association of polymorphic variants of CYP2C19 (G681A), P2RY12 (H1/H2), ITGB3 (T1565C), ITGA2 (C807T), eNOS3 (T786C) genes with high residual platelet reactivity (HRPR) to clopidogrel and acetylsalicylic acid (ASA) at different terms of myocardial infarction (MI).Material and methods. The study included 400 patients with MI aged 31-74 years, 317 (79,3%) men and 83 (20,7%) women. Platelet aggregation performed on days 1-2, 12-14 and 28-30 of MI, and genotyping by the polymerase chain reaction were analyzed using the STATISTICA 10.0 program.Results. Differences were found in ADP-test 1-3 depending on the CYP2C19 (G681A) polymorphism, ADP-test 1 depending on the P2RY12 (H1/H2) polymorphism, ADP-test 2 depending on the ITGB3 (T1565C) polymorphism, ASPI-test 1 depending on the eNOS (T786C) polymorphism. The risk of HRPR to clopidogrel is higher in 681A CYP2C19 allele carriers compared to the G681 carriers throughout the entire observation period: initially odds ratio (OR) of 1,8 (1,14-2,88), p=0,012, on days 12-14 of MI, OR of 1,7 (1,08-2,68), p=0,023 and on days 28-30 of MI, OR of 2,3 (1,42-3,81), p=0,0008. The risk of HRPR to clopidogrel is higher in AA CYP2C19 genotype carriers compared to GG genotype carriers, on days 1-2 of MI (OR 6,5 (1,16-36,4), p=0,033), on days 28-30 of MI (OR 7,8 (1,26-48,0), p=0,027). The risk of HRPR to clopidogrel on days 1-2 of MI is higher in H2 P2RY12 locus carriers compared to H1 locus carriers (OR 1,5 (1,02-2,22), p=0,039). The risk of HRPR to ASA on days 1-2 of MI is higher in the 786C eNOS3 allele carriers compared to T786 allele carriers (OR 1,4 (1,02-1,96), p=0,036). Carriers of haplotypes of minor alleles of CYP2C19 + ITGA2 + P2RY12 + eNOS genes (OR 3,9 (1,13-13,65), p=0,032) and CYP2C19 + ITGA2 + eNOS genes (OR 5,1 (1,7214,96), p=0,0032) have higher risk of HRPR to dual antiplatelet therapy (DAPT) on days 28-30 of MI compared to the rest of patients.Conclusion. The association of HRPR to clopidogrel with the CYP2C19 (G681A) polymorphism was found during the entire observation period, with the P2RY12 (H1/H2) polymorphism on days 1-2 of MI, with the ITGB3 (T1565C) polymorphism on days 10-12 of MI. The association of HRPR to ASA with eNOS (T786C) polymorphism was found on days 1-2 of MI. Minor allele haplotypes of the CYP2C19 + ITGA2 + P2RY12 + eNOS genes and CYP2C19 + ITGA2 + eNOS genes were associated with a higher risk of developing HRPR to DAPT on days 28-30 of MI.