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

Fibrinogen synthesis is stimulated by proinflammatory triggers and depends on α-, ß- 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.

Association of angiotensin-converting enzyme intron 16 insertion/deletion polymorphism with history of foetal loss.

INTRODUCTION: The angiotensin-converting enzyme (ACE) intron 16 insertion/deletion (I/D) polymorphism is associated with ACE activity and has been discussed as a risk factor for pre-eclampsia. Disturbances of uteroplacental circulation are involved in the pathogenesis of pre-eclampsia. In this study, we tested whether the ACE I/D genotype is associated with history of foetal loss (FL) or uteroplacental dysfunction (UPD). PATIENTS AND METHODS: ACE I/D genotype was determined in 312 women presenting with a history of FL and 112 women admitted because of UPD. The association of the ACE I/D genotype with FL or UPD was assessed in a case-control study using 527 patients with diagnoses other than FL or UPD. To exclude potential biases due to associations of this genotype with other diagnoses, we additionally performed a case-control study using 553 healthy controls. RESULTS: ACE I/D genotype was significantly associated with history of FL in both case-control studies (patient controls: odds ratio 1.52, p<0.02; healthy controls: odds ratio 1.48, p=0.02). There was no evidence for allele-dose dependency. No association of the ACE I/D genotype with UPD could be detected. CONCLUSIONS: The ACE I/D genotype exhibits a statistically significant association with a history of FL. These results corroborate an involvement of the renin-angiotensin system in pregnancy complications.