Association of Genetic Polymorphisms of Fibrinogen, Factor XIII A-Subunit and α2-Antiplasmin with Fibrinogen Levels in Pregnant Women

Abstract

Fibrinogen synthesis is stimulated by proinflammatory triggers and depends on α-, β- and γ-fibrinogen (FGA, FGB, FGG) genotypes. Constellations of fibrinogen, factor XIII A-subunit (F13A) and α₂-antiplasmin (A2AP) genotypes predisposing for dense fibrin gels with high antifibrinolytic capacity (e.g., FGB rs1800790 A-allele carriage in F13A 34Val/Val or A2AP 6Arg/Arg wildtypes) are related with reduced inflammation. As both relationships are likely to influence each other, we tested whether the association of fibrinogen genotypes with fibrinogen levels is influenced by F13A and A2AP genotypes in a population under proinflammatory stress. In total, 639 women were followed during pregnancy (2218 observations). The relationship between fibrinogen genotypes and levels was statistically assessed in univariate and multivariate analyses without and with stratification for F13A Val34Leu and A2AP Arg6Trp. Strong associations with fibrinogen levels could be found for FGB rs1800790G > A, FGA rs2070016T > C and FGG rs1049636T > C. For FGB rs1800790G > A and FGA rs2070016T > C, this relationship significantly depended on F13A Val34Leu and A2AP Arg6Trp genotypes. Specifically, in F13A 34Val/Val wildtypes, carriage of FGB rs1800790A was related to significantly lower fibrinogen levels compared with FGB rs1800790GG wildtypes (p < 0.01). For A2AP 6Arg/Arg wildtypes, a comparable relationship could be found (p < 0.04). As these genotype constellations related to lower fibrinogen levels have previously been shown to be associated with reduced inflammatory activity, these findings suggest that the influence of fibrinogen, F13A and A2AP genotypes on inflammation could affect the control of fibrinogen levels and vice versa.

Keywords: factor XIII; fibrin crosslinking; fibrinogen; genotype; inflammation; pregnancy; α2-antiplasmin.