Genetic basis of variation in fibrinogen and CRP

Elevated plasma fibrinogen is a risk factor for coronary artery disease. There is uncertainty about the size of the genetic contribution to plasma fibrinogen, and although an association has been reported between fibrinogen gene polymorphisms and plasma fibrinogen level in population-based studies, this finding has been inconsistent. There is strong evidence for association between C-reactive protein (CRP) and vascular disease, but the genetic contribution to the variance of CRP level is unknown. Using a family-based study design, we sought to: (1) determine the heritability of plasma fibrinogen and CRP, and (2) to elucidate whether variants in the fibrinogen gene are involved in the control of plasma fibrinogen and CRP levels by linkage analysis of plasma levels using using polymorphisms at the fibrinogen locus as genetic markers. 561 members of 98 Caucasian extended families were studied. Haplotypes of two β-fibrinogen promoter variants (β-455 G/A, β-854 G/A) and genotypes of an intragenic microsatellite marker in the α-fibrinogen gene were determined by PCR. Genetic linkage between the fibrinogen gene variants and plasma fibrinogen and CRP levels were evaluated with the SOLAR variance-component linkage method. The estimated heritability of plasma fibrinogen was low at 0.22 ± 0.08, p = 0.0007, although the heritability of CRP was higher, 0.38 ± 0.08, p < 0.0000001. The proportion of variance in plasma fibrinogen and CRP explained by age, sex, cigarette smoking, and body mass index was 0.24 and 0.42 respectively. There was no evidence of genetic linkage between the fibrinogen gene and levels of plasma fibrinogen or CRP. These results, in the largest such quantitative linkage study of these questions performed to date, show that the contribution of the fibrinogen locus to the variance of fibrinogen and CRP levels is likely to be small, and thus family-based association approaches will be required to define the genetic variant(s) responsible for the observed population associations. The high heritability of CRP suggests its suitability as a phenotype for quantitative genome-wide linkage studies of cardiovascular risk.