CYP2C19 and ABCB1 polymorphisms in patients of Chuvash ethnic group: assessment of clopidogrel resistance and associations with recurrent myocardial infarction

Abstract

Background. The prevalence of clopidogrel resistance among patients with cardiovascular diseases (CVD) reaches 30–40 %, significantly increasing the risk of recurrent myocardial infarction (MI) and other thrombotic events. Genetic polymorphisms in CYP2C19 and ABCB1 account for up to 40 % of the variability in antiplatelet response; however, data on Turkic populations, including the Chuvash, remain fragmentary. Objective. To determine the frequencies of CYP2C19 (*2, *3, *17) and ABCB1 C3435T polymorphisms, as well as their association with recurrent MI and clopidogrel resistance in patients of Chuvash ethnic origin with CVD, including acute coronary syndrome (ACS). Materials and methods. This prospective cohort study included 216 Chuvash patients (mean age 66.5 years) with CVD, including ACS, receiving dual antiplatelet therapy with clopidogrel. Genotyping of CYP2C19 (*2, *3, *17) and ABCB1 (3435C>T) polymorphisms was performed using real-time PCR. In a subgroup of ACS patients (n=30), ADP-induced platelet aGGreGAtion was assessed turbidimetrically on day 7 of therapy. Results. Among Chuvash patients, a high frequency of minor alleles was observed: ABCB1 C3435T — 60.6 %, CYP2C1917 (–806C>T) — 28.7 %, whereas the frequencies of CYP2C192 and CYP2C193 were low (9.05 % and 1.85 %, respectively). Heterozygous CT genotype of CYP2C19*17 was associated with a higher rate of recurrent MI both in the overall cohort (19.8 % vs. 8.5 % in CC carriers; p=0.049) and in the ACS subgroup (30.2 % vs. 12.9 %; p=0.037, p~CC–CT~ =0.044). Laboratory platelet aGGreGAtion assessment revealed that the highest proportion of antiplateletresistant patients was observed among heterozygotes carrying the *1/*17 genotype (rapid metabolizer phenotype), whereas no resistance cases were recorded among *17/*17 homozygotes (ultrarapid metabolizers). No statistically significant associations with recurrent MI were found for CYP2C192, CYP2C193, or ABCB1 polymorphisms. Conclusion. In Chuvash patients with CVD, including ACS, heterozygous carriage of CYP2C1917 is associated with recurrent MI, which contradicts the expected enhancement of clopidogrel antiplatelet effect (rapid metabolizer phenotype). This may indicate possible phenoconversion due to the interplay of genetic factors (ABCB1 C3435T) and drug — drug interactions (concomitant omeprazole use).