RESUMO
Atherosclerotic coronary artery disease (CAD) and myocardial infarction (MI) as its most severe clinical complication remain the leading causes of mortality in the majority of countries. Despite the progress in the treatment of MI, quite often the patients, after the first-time MI, develop subsequently a variety of adverse cardiovascular events. In this retrospective study we evaluated the contribution of allelic variations in 9p21.3 locus and in 21 atherogenesis-related genes to the development of hard cardiac events in a cohort of patients of Russian ethnicity after the first acute MI during long-term follow-up (7-10â¯years). Death from cardiac causes and recurrent nonfatal MI were considered as key clinical outcomes. We have shown the association of rs1333049 and rs10757278 in 9p21.3 and MTHFR rs1801133 with recurrent unfavorable events, the latter was observed in time-dependent manner. Multilocus analysis additionally suggested the influence of carriage of the CRP and ENOS genes variants at the development of subsequent adverse events after MI. The composite model built for prediction of the individual genetic risk of postinfarction hard cardiac events included 9p21.3 rs1333049*GG and MTHFR*TT and was characterized by area under the curve (AUC)â¯=â¯0.65. Our data show that 9p21.3 locus and MTHFR gene polymorphisms could influence long-term prognosis of recurrent hard cardiac events in patients who underwent the first MI. It is possible that addition of genotyping at such loci to existing clinical scores could improve their predictability.
Assuntos
Aterosclerose/genética , Cromossomos Humanos Par 9/genética , Infarto do Miocárdio/genética , Polimorfismo Genético/genética , Alelos , Doença da Artéria Coronariana/genética , Feminino , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Federação RussaRESUMO
Epidemiological genetics established that heritability in determining the risk of myocardial infarction (MI) is substantially greater when MI occurs early in life. However, the genetic architecture of early-onset and late-onset MI was not compared. We analyzed genotype frequencies of SNPs in/near 20 genes whose protein products are involved in the pathogenesis of atherosclerosis in two groups of Russian patients with MI: the first group included patients with age of first MI onset <60 years (N = 230) and the second group with onset ≥60 years (N = 174). The control group of corresponding ethnicity consisted of 193 unrelated volunteers without cardiovascular diseases (93 individuals were over 60 years). We found that in the group of patients with age of onset <60 years, SNPs FGB rs1800788*T, TGFB1 rs1982073*T/T, ENOS rs2070744*C and CRP rs1130864*T/T were associated with risk of MI, whereas in patients with age of onset ≥60 years, only TGFB1 rs1982073*T/T was associated with risk of MI. Using APSampler software, we found composite markers associated with MI only in patients with early onset: FGB rs1800788*T + TGFB1 rs1982073*T; FGB rs1800788*T + LPL rs328*C + IL4 rs2243250*C; FGB rs1800788*T + ENOS rs2070744*C (Fisher p values of 1.4 × 10-6 to 2.2 × 10-5; the permutation p values of 1.1 × 10-5 to 3.0 × 10-4; ORs = 2.67-2.54). Alleles included in the combinations were associated with MI less significantly and with lower ORs than the combinations themselves. The result showed a substantially greater contribution of the genetic component in the development of MI if it occurs early in life, and demonstrated the usefulness of genetic testing for young people.
Assuntos
Aterosclerose/genética , Infarto do Miocárdio/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Alelos , Biomarcadores/sangue , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Federação RussaRESUMO
BACKGROUND: In 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 RESULTS: In 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. CONCLUSIONS: The 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.