BackgroundIn spite of progress in cardiovascular genetics, data on genetic background of myocardial infarction are still limited and contradictory. This applies as well to the genes involved in inflammation and coagulation processes, which play a crucial role in the disease etiopathogenesis.Methods and ResultsIn this study we found genetic variants of TGFB1, FGB and CRP genes associated with myocardial infarction in discovery and replication groups of Russian descent from the Moscow region and the Republic of Bashkortostan (325/185 and 220/197 samples, correspondingly). We also found and replicated biallelic combinations of TGFB1 with FGB, TGFB1 with CRP and IFNG with PTGS1 genetic variants associated with myocardial infarction providing a detectable cumulative effect. We proposed an original two-component procedure for the analysis of nonlinear (epistatic) interactions between the genes in biallelic combinations and confirmed the epistasis hypothesis for the set of alleles of IFNG with PTGS. The procedure is applicable to any pair of logical variables, e.g. carriage of two sets of alleles. The composite model that included three single gene variants and the epistatic pair has AUC of 0.66 both in discovery and replication groups.ConclusionsThe genetic impact of TGFB1, FGB, CRP, IFNG, and PTGS and/or their biallelic combinations on myocardial infarction was found and replicated in Russians. Evidence of epistatic interactions between IFNG with PTGS genes was obtained both in discovery and replication groups.

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Carriage frequencies of alleles and genotypes of theTGFB1 gene polymorphous loci –509C>T (rs1800469), 869T>C (rs1982073), 915G>C (rs1800471), which affect the level of cytokine TGF-β1 production, were analyzed in the patients of Russian ethnic descent with myocardial infarction (MI) (406 cases) and in the control group of the same ethnic descent (198 controls). Significant association with MI was observed in carriage frequencies of the alleleTGFB1*–509T (p=0.046, OR =1.45, 95% CI: 1.02-2.06), genotypes TGFB1*869T/T (p=0.0024, OR =1.75, 95% CI: 1.22-2.51), andTGFB1*915G/G (p=0.048, OR=1.76, 95% CI: 1.05-2.97). Linkage disequilibrium analysis for these SNPs has shown that the associations revealed can be considered to be independent. A complex analysis of MI association with combinations of alleles/genotypes of said SNPs indicates their cumulative effect. An analysis of susceptibility to early-onset MI (≤ 50 years old) revealed a positive association of the alleleTGFB1*–509T (p=0.002, OR=2.24, 95% CI: 1.35-3.71) and genotypeTGFB1*869T/T (p=0.008, OR=1.93, 95% CI: 1.18-3.15), as well as their additivity. An analysis of susceptibility to recurrent MI revealed an association of the genotypeTGFB1*–509T/T (p=0.0078, OR=2.60, 95% CI: 1.28-5.28). The results obtained indicate the important role of theTGFB1gene in susceptibility to MI, including early-onset and recurrent MI, in Russians.