Combined Segregation and Linkage Analysis of Fibrinogen Variability in Israeli Families: Evidence for Two Quantitative-trait Loci, One of Which is Linked to a Functional Variant (−58G > A) in the Promoter of the α-fibrinogen Gene

The association of α‐ and β‐fibrinogen polymorphisms with plasma fibrinogen levels was examined in a sample of 452 family members from 80 Israeli kindreds. The measured genotype analysis indicated that the β‐fibrinogen ?455G > A polymorphism was not associated with fibrinogen levels, while the α‐fibrinogen ?58G > A locus showed a significant association with fibrinogen levels (χ²= 17.7; df = 3; p < 0.001) , with the ?58A allele being associated with higher levels. Segregation analysis in this sample suggested a recessive quantitative‐trait locus (QTL) with a major effect that controlled the sex‐ and age‐adjusted fibrinogen levels. Results from a combined segregation/linkage analysis indicated that a single QTL influencing plasma fibrinogen is in gametic equilibrium with the β‐fibrinogen ?455G > A and α‐fibrinogen ?58G > A polymorphisms. An extended analysis with a two‐QTL model significantly improved the fit of the model (p ≤ 0.001) , and gave support for linkage between the fibrinogen QTL and the α‐fibrinogen polymorphism. In vitro analysis with a DNA fragment containing this variant, linked to a reporter gene, showed 2‐fold higher expression of the A allele compared to the G allele in the liver cell line HepG2, both under basal conditions and after stimulation with interleukin 6. These results demonstrate that two QTLs are jointly involved in determining plasma fibrinogen levels in this sample of families, one of which is located close to a functional variant in the α‐fibrinogen locus.