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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.

SUBMITTER: Schwedler C

PROVIDER: S-EPMC8703568 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:The identification of variants in the nicotinic acetylcholine receptor (nAChR) subunit genes associated with smoking phenotypes are increasingly important for prevention and treatment of nicotine dependence. In the context of personalized medicine, the aims of this study were to evaluate whether cholinergic receptor nicotinic alpha 2 (CHRNA2), cholinergic receptor nicotinic alpha 3 (CHRNA3), cholinergic receptor nicotinic alpha 5 (CHRNA5) and cholinergic receptor nicotinic beta 3 (CHRNB3) polymorphisms were associated with nicotine dependence severity, and to investigate possible pharmacogenetics markers of smoking cessation treatment. METHODS:This study cohort enrolled 1049 smoking patients who received pharmacological treatment (varenicline, varenicline plus bupropion, bupropion plus/or nicotine replacement therapy). Smoking cessation success was considered for patients who completed 6 months of continuous abstinence. Fagerström test for nicotine dependence (FTND) and Issa situational smoking scores (Issa score) were analyzed for nicotine dependence. CHRNA2 (rs2472553), CHRNA3 (rs1051730), CHRNA5 (rs16969968 and rs2036527) and CHRNB3 (rs6474413) polymorphisms were genotyped by high resolution melting analysis. RESULTS:Females with GA and AA genotypes for CHRNA5 rs16969968 and rs2036527 polymorphisms had higher success rate in smoking cessation treatment: 44.0% and 56.3% (rs16969968), 41.5% and 56.5% (rs2036527), respectively, compared with carriers of the GG genotypes: 35.7% (rs16969968), 34.8% (rs2036527), (P?=?0.03, n?=?389; P?=?0.01, n?=?391). The GA or AA genotypes for the rs16969968 and rs2036527 were associated with higher odds ratio for success in women (OR?=?1.63; 95% CI?=?1.04 to 2.54; P?=?0.03 and OR?=?1.59, 95% CI?=?1.02 to 2.48; P?=?0.04; respectively). We did not find association of these polymorphisms with nicotine dependence related scores. Polymorphisms in the CHRNA2, CHRNA3 and CHRNB3 genes were not associated with the phenotypes studied. CONCLUSION:CHRNA5 rs16969968 and rs2036527 were associated with higher success rate in the smoking cessation treatment in women. These findings might contribute to advances in personalized medicine.

Project description:Essentials Delayed treatment with tranexamic acid results in loss of efficacy and poor outcomes. Increasing urokinase activity may account for adverse effects of late tranexamic acid treatment. Urokinase + tranexamic acid produces plasmin in plasma or blood and disrupts clotting. α2 -Antiplasmin consumption with ongoing fibrinolysis increases plasmin-induced coagulopathy. SUMMARY: Background Tranexamic acid (TXA) is an effective antifibrinolytic agent with a proven safety record. However, large clinical trials show TXA becomes ineffective or harmful if treatment is delayed beyond 3 h. The mechanism is unknown but urokinase plasminogen activator (uPA) has been implicated. Methods Inhibitory mechanisms of TXA were explored in a variety of clot lysis systems using plasma and whole blood. Lysis by tissue plasminogen activator (tPA), uPA and plasmin were investigated. Coagulopathy was investigated using ROTEM and activated partial thromboplastin time (APTT). Results IC50 values for antifibrinolytic activity of TXA varied from < 10 to > 1000 μmol L-1 depending on the system, but good fibrin protection was observed in the presence of tPA, uPA and plasmin. However, in plasma or blood, active plasmin was generated by TXA + uPA (but not tPA) and coagulopathy developed leading to no or poor clot formation. The extent of coagulopathy was sensitive to available α2 -antiplasmin. No clot formed with plasma containing 40% normal α2 -antiplasmin after short incubation with TXA + uPA. Adding purified α2 -antiplasmin progressively restored clotting. Plasmin could be inhibited by aprotinin, IC50 = 530 nmol L-1 , in plasma. Conclusions Tranexamic acid protects fibrin but stimulates uPA activity and slows inhibition of plasmin by α2 -antiplasmin. Plasmin proteolytic activity digests fibrinogen and disrupts coagulation, exacerbated when α2 -antiplasmin is consumed by ongoing fibrinolysis. Additional direct inhibition of plasmin by aprotinin may prevent development of coagulopathy and extend the useful time window of TXA treatment.

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

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Dataset Information

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

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OmicsDI is part of the ELIXIR infrastructure

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