The Functional effects of the -455GA polymorphism on the IL-6-induced expression of the β-fibrinogen gene may be due to linkage disequilibrium with other functional polymorphisms

Elevated plasma fibrinogen levels have been identified as an independent risk factor for coronary heart diseases, stroke and peripheral artery disease. The -455GA polymorphism in the promoter region of the β-fibrinogen gene has been associated with increased plasma fibrinogen levels. However, the functional effect of this polymorphism has been controversial and other polymorphisms in the fibrinogen gene have also been implicated in higher fibrinogen levels. In this study, we evaluated the transcriptional activity of 4 natural haplotypes and 6 artificial haplotypes in the promoter region of the β-fibrinogen gene. Significantly lower IL-6-induced activity was observed in the -1420A and -148T alleles. In contrast, the -854A allele had significantly higher activity. Artificial haplotypes containing the -1420A, -854A and -148T alleles were also analyzed to confirm individual functional effects. The -1420A and -148T alleles significantly lowered the activities, while the -854A allele significantly raised the activity. From this study we conclude that the -1420GA, -854GA and -148CT polymorphisms in the β-fibrinogen promoter region are functional polymorphisms while the -455GA polymorphism may not be a functional one, and that the association of the -455GA polymorphism with higher fibrinogen levels may actually be due to linkage disequilibrium between the -455GA polymorphism and other truly functional polymorphisms.