Evidence for a quantitative trait locus for plasma fibrinogen from a family–based association study

Studies in unrelated individuals have shown an association between fibrinogen gene polymorphisms and plasma fibrinogen levels, which is itself a risk factor for coronary heart disease. Family-based studies have complementary strengths in the investigation of such hypothesized genetic associations. Genotypes at the β-fibrinogen -455G/A promoter polymorphism, and a neighbouring highly polymorphic microsatellite in the α-fibrinogen gene were examined for evidence of genetic linkage and association with plasma fibrinogen in 568 members of 97 Caucasian families. The heritability of plasma fibrinogen was 0.22 ± 0.08, P = 0.0007. There was no significant evidence of genetic linkage between the fibrinogen locus and plasma fibrinogen with either marker. In contrast, there was evidence for association of plasma fibrinogen with genotype at the β-455G/A polymorphism (χ₁² = 11.12; P = 0.0009). Tests examining allelic transmission from heterozygous parents confirmed this association (Monk’s test, T = 2.17; P = 0.03). Genotype at the β-455G/A polymorphism accounted for 2% of the observed variation in fibrinogen. This is equivalent to about 10% of the heritable component, suggesting the presence of other quantitative trait loci (QTL) in unlinked genes. Confirmation of the association of plasma fibrinogen with genotype at the β-455G/A polymorphism in families indicates that the association is due to the physical proximity of this marker to a QTL, although the effect of this QTL was too small to be detected by linkage in this study. These findings are of potential importance for the design of genetic studies of multifactorial quantitative traits.