Variants of the Coagulation and Inflammation Genes Are Replicably Associated with Myocardial Infarction and Epistatically Interact in Russians

Abstract

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.

Multilocus Analysis of Genetic Susceptibility to Myocardial Infarction in Russians: Replication Study

“…In order to answer the question what is the reason for the cumulative effect of the alleles of different genes (whether it is the summation of small mutually independent contributions of individual alleles or epistatic interactions between these alleles), we analyzed the three-way interactions using the statistical approach described earlier [6]. The synergy factor (SF) with 95% CI and the p values calculated using the exact three-way test, similar to the OR with 95% CI and the p value determined by standard evaluation of the associations between the phenotype and the genotype (i.e., using the two-way Fisher's test), were not significant.…”

“…We would like to mention that the model does not become more efficient if the MTHFR and the 9p21 region alleles, which are the components of the combinations identified by APsampler, are added one by one. These findings were used to improve the earlier built composite genetic model of the risk of MI, which includes the TGFB1, FGB, and CRP genetic variants and the epistatic combination of the IFNG and PTGS1 genes as predictors [6]. Figure 3B shows three ROC curves: the ROC curve obtained in the analyzed sample for the composite model described in [6]; the ROC curve for the carriage of a combination of the newly identified markers shown in Fig.…”

“…An SNP was considered to be myocardial infarction-associated when the association was significant either in the recessive or the dominant model. The earlier proposed approach [6] was used to reveal possible non-linear interactions (epistasis) between alleles in the identified biallelic combinations: the syn-ergy factor (SF) was determined [22] and the p values were calculated using the exact three-way interaction test [21]. The interaction between the alleles was considered to be epistatic if the p value was less than 0.05 and the 95% CI value for SF did not cross 1.…”

“…prognostic efficacy of the identified markers both one by one and along with the markers identified previously [6]. Genomic typing was performed using the polymerase chain reaction (PCR)-based methods.…”

Multilocus Analysis of Genetic Susceptibility to Myocardial Infarction in Russians: Replication Study

“…The nature of this effect was also studied. Furthermore, we evaluated the prognostic efficacy of the identified markers both one by one and along with the markers identified previously [6]. Genomic typing was performed using the polymerase chain reaction (PCR)-based methods.…”