Fibrinogen genotypes and their impact on recurrence of venous thromboembolism and family history: A prospective population-based study.

Venous thromboembolism (VTE) involves blood clot formation in veins, resulting in serious health issues. Fibrinogen, a crucial clotting protein, consists of three polypeptides encoded by the fibrinogen genes: alpha (FGA), beta (FGB) and gamma (FGG). We genotyped most common missense variants in the fibrinogen genes in relation to VTE, recurrence and family history in Malmö Thrombophilia Study, including 1465 VTE patients followed for ~10 years and 429 healthy donors. FGG (rs6063) was significantly associated with increased odds of primary VTE (odds ratio [OR] = 8.2; 95% confidence interval [CI] = 1.05-63.6) after adjusting for age and sex. For recurrent VTE, Cox-regression analysis indicated a higher risk associated with FGA (rs6050) (hazard ratio [HR] = 1.8; 95% CI = 1.1-2.8), with even greater risk for unprovoked recurrent VTE (HR = 2.3; 95% CI = 1.3-4.2), surpassing the well-known factor V Leiden (FVL) (HR = 1.9; 95% CI = 1.2-3.0). Combining risk alleles from FVL and FGA (rs6050) significantly raised the risk for unprovoked recurrent VTE: ≥3 risk alleles (HR = 4.6; 95% CI = 1.9-11.3), two risk alleles (HR = 2.6; 95% CI = 1.4-4.8) and one risk allele (HR = 1.5; 95% CI = 0.8-2.7) compared to 0 risk allele. Prevalence of FGA (rs6050) risk allele was significantly higher in cases with a family history of VTE. We propose FGA (rs6050) as a novel predictor for unprovoked recurrent VTE and it may contribute to the familial occurrence of VTE.