Haplotypes of the fibrinogen gene and cerebral small vessel disease: The Rotterdam scan study
Objective: Fibrinogen levels and fibrinogen clot structure have been implicated in the pathogenesis of vascular disease. We examined fibrinogen levels and variation in fibrinogen genes (fibrinogen γ (FGG), α (FGA) and β (FGB)), which have been associated with fibrin clot structure and fibrinogen levels, in relation to cerebral small vessel disease (SVD). Methods and results: This study was performed as part of the Rotterdam Scan Study, a population based study in 1077 elderly patients undergoing cerebral MRI. Plasma fibrinogen levels and haplotypes were determined. We examined the association between fibrinogen levels and haplotype with silent brain infarcts and white matter lesions using logistic regression models. We constructed seven haplotypes (frequency >0.01) that describe the total common variation in the FGG and FGA genes. Haplotype 2 (GATAGTG) was associated with the presence of silent brain infarcts compared with the most frequent haplotype (GGTGGTA) (OR 1.41, 95% CI 1.03 to 1.94). Haplotype 3 (GGCGATA) was associated with periventricular white matter lesions in the highest fertile of the distribution (OR 1.40, 95% CI 1.01 to 1.92). No association was found between plasma fibrinogen levels and SVD. Conclusions: Our study provides evidence for an association of common variation in the FGG and FGA genes with cerebral SVD. It is possible that the structure of the fibrin clot rather than plasma fibrinogen levels plays a role in the pathogenesis of cerebral SVD.