The association between fibrinogen haplotypes and myocardial infarction in men is partly mediated through pleiotropic effects on the serum IL-6 concentration

Background and objectives. Fibrinogen haplotypes have been associated with risk of myocardial infarction (MI), independently of plasma fibrinogen concentration, and experimental data indicate that fibrinogen exerts pleiotropic effects on interleukin 6 (IL-6) production. Also, the coagulation factor XIII (gene symbol F13A1) Val34Leu haplotype tag single nucleotide polymorphism (htSNP) has been reported to exert pleiotropic effects on serum IL-6 concentration and to be associated with risk of MI. Therefore, in the present case-control study (a substudy to the Stockholm Heart Epidemiology Program), the effects of the fibrinogen gamma (FGG) 9340T > C [rs1049636], fibrinogen alpha (FGA) 2224G > A [rs2070011] and F13A1 Val34Leu [rs5985] htSNPs on concentrations of plasma fibrinogen and serum IL-6 and risk of MI were assessed. Results. There were no associations between these SNPs and the plasma fibrinogen concentration. In contrast, in male controls the FGA 2224G > A htSNP was significantly associated with serum IL-6 concentration (P < 0.05). Also, in men the FGG-FGA*1 haplotype (containing the major FGG 9340T and FGA 2224G alleles) was associated with increased risk of MI [adjusted odds ratio (OR) 95% confidence interval (CI): 1.29 (1.02, 1.62)] and with higher IL-6 concentrations, whereas the least common FGG-FGA*4 haplotype (containing the minor FGG 9340C and FGA 2224A alleles) conferred lowered risk [adjusted OR (95% CI): 0.70 (0.57, 0.86)] and lowered IL-6 concentrations. In women, fibrinogen haplotypes were not associated with risk of MI after adjusting for cardiovascular risk factors. Conclusion. In healthy men, fibrinogen haplotypes are associated with serum IL-6 concentrations in a manner consistent with their impact on MI risk.