Возможные генетические предикторы развития сердечно-сосудистых осложнений после коронарного шунтирования

Abstract

to investigate associations of single nucleotide polymorphisms (SNPs) rs2046934, rs1126643, rs5918, rs6065, rs4244285; rs4986893 with cardiovascular complications (CVC) in patients after CABG. We enrolled in this study 130 patients with stable functional class II-IV angina. After CABG 69 patients received ASA (100 mg of enteric form), 61 patients received dual antiplatelet therapy (ASA 100 mg + clopidogrel 75 mg). Mean follow up period was 10.9±5.2 months. The primary composite endpoint included all-cause mortality, myocardial infarction (MI), and ischemic stroke. The control group comprised 185 healthy volunteers. Platelet function was assessed using light transmission aggregometry with ADP (5μM) and arachidonic acid (1 mM). The following single nucleotide polymorphisms (SNPs) were identified by real-time PCR: rs2046934 (H1/H2) on P2RY12 [encoding platelet ADP receptor] (n=100); rs1126643 (C807T, Phe224Phe) on ITGA2 [encoding collagen receptor] (n=87); rs5918 (176T>C, Leu33Pro) on ITGB3 [encoding fibrinogen receptor) (n=91); rs6065 (Thr145Met) on GP1BA [encoding platelet receptor for Von Willebrand factor] (n=114); rs4244285 (*2) (n=84), and rs4986893 (*3) (n=83) on СYP2C19 [encoding cytochrome P450 activity]. The prevalence of rs5918, rs6065, rs4244285, rs4986893, rs2046934 did not differ significantly between patients and healthy volunteers. The mutant allele (T) of ITGA2 was detected more often in healthy volunteers: 67.2 % vs 51.7 % (р=0.021). Before and after CABG there was no significant difference in platelet aggregation between carries and non-carries of the mutant ITGA2 allele. Number of CVCs registered during follow-up was 12: 3 strokes, 6 MIs, 3 deaths. Patients with composite mutant alleles of ITGB3+СYP2C19*2 or СYP2C19*2+ITGA2, and with the mutant allele (*2) of СYP2C19 met end points more often than patients with other gene combinations (wild type homozygotes, presence of one mutant allele of ITGB3 or ITGA2, the composite of mutant alleles of ITGB3+ITGA2 or ITGB3+ITGA2+ СYP2C19*2) (hazard ratio 4.0, 95 % confidence interval 2,19-7.29, р=0.008). Carriers of ITGB3 mutant allele showed higher AA-induced platelet reactivity on the 1st-3rd day after CABG. Amplitude of platelet aggregation in carriers of mutant allele was 27.5 % vs 12.7 % in wild type (p=0.016). No differences in platelet reactivity among carriers of other mentioned mutant alleles and wild types were observed. Carriage of the combination of mutant alleles ITGB3+СYP2C19*2 or СYP2C19*2+ITGA2 or СYP2C19*2 is possible predictor of CVC in patients after CABG.