Fibrinogen Alpha and Gamma Genes and Factor V^Leiden in Children with Thromboembolism: Results from Two Family-Based Association Studies

Background: Fibrinogen, the precursor of fibrin, is an essential component of the hemostatic system. A previous large case-control study showed that genetic variation in the fibrinogen gamma gene (FGG) increased the risk for VT in adults. We investigated the association of haplotypes comprising the fibrinogen alpha (FGA) and gamma (FGG) genes, carriership of the Factor V^Leiden-mutation and risk for VT in two large family-based study samples for pediatric thromboembolism.

Methods: We genotyped 7 single nucleotide polymorphisms in FGA and FGG, and the G1691A Factor V^Leiden polymorphism in 244 pediatric VT and 268 thrombo-embolic stroke families. Association was assessed using the Transmission Disequilibrium Test (TDT) and corrected for multiple testing.

Results: Association analysis revealed that the FGA-H1 haplotype, and the FGG-H2 and -H3 haplotypes, were significantly associated with VT (FGA-H1, P=0.05; FGG: H2, P=0.032; H3, P=0.0216). In an independent study sample, FGA-H1 (P=0.0085) and FGG-H2 (P=0.05) were significantly associated with TS. When stratifying for FV^Leiden carriership, the association between FGA and FGG and VT was more pronounced in FV^Leiden-negative families (FGA-H1, P=0.0006; FGG-H2, P=0.0005). Homozygous carriership of the FGG-H2 risk haplotype resulted in the lowest fibrinogen γ′ content (γ′ levels: 22.7±13.7 vs. 26.8±12.0, P=0.013; % γ′: 7.63±3.05 vs. 9.46±3.17, P=2.3×10⁻⁵), with increasing concentrations of fibrinogen γ′ in heterozygote H2 carriers. Compound heterozygote carriers of one FGG-H2 risk and one FGG-H3 protective haplotype, showed significant increase in fibrinogen γ′ (P=0.000032), while fibrinogen levels remained unchanged. In contrast, homozygote carriers of the protective FGG-H3 haplotype showed the highest concentration of fibrinogen γ′ content (% γ′: 9.21±3.09, P=0.0031) with decreased total fibrinogen levels.

Conclusion: Our results support an important role of genetic variants in FGA and FGG in thromboembolism in children and adults. Our data further suggest that the genetic architecture of VT is complex and involves subtle influences through susceptibility and protective haplotypes in FGG and a genetic interaction with the FV^Leiden-mutation.