Abstract
Interleukin-6 (IL-6) induces the expression of fibrinogen, and polymorphic variation within the fibrinogen genes is believed to alter the magnitude of this expression. The identification of the functional relevance of individual fibrinogen single nucleotide polymorphisms (SNPs) has been hindered by the high linkage disequilibrium (LD) reported in the European fibrinogen gene locus. This study investigated two novel and 12 known fibrinogen SNPs of potential functional relevance, in 2010 Tswana individuals known to have low LD. We aimed to identify functional polymorphisms that contribute to clot-related phenotypes and total and γ’ fibrinogen concentrations independently and through their interaction with IL-6, by taking advantage of the high fibrinogen and IL-6 concentrations and the low LD reported in black South Africans. Fibrinogen was significantly associated with IL-6, thereby mediating associations of IL-6 with clot formation and structure, although attenuating the association of IL-6 with clot lysis time. None of the common European fibrinogen haplotypes was present in this study population. Putative functional fibrinogen SNPs FGB–rs7439150, rs1800789 (–1420G/A) and rs1800787 (–148C/T) were significantly associated with fibrinogen concentration and altered clot properties, with several associations significantly influenced by IL-6 concentrations. The impact of harbouring several minor fibrinogen SNP alleles on the association of IL-6 and fibrinogen concentration was cumulative, with possession of each additional minor allele showing a stronger relationship of IL-6 with fibrinogen. This was also reflected in differences in clot properties, suggesting potential clinical relevance. Therefore, when investigating the effect of fibrinogen genetics on fibrinogen concentrations and CVD outcome, the possible interactions with modulating factors and the fact that SNP effects seem to be additive should be taken into account.
Highlights
Fibrinogen is central to blood coagulation and the inflammatory response
We aimed to identify functional polymorphisms that contribute to clot-related phenotypes and total and γ’ fibrinogen concentrations independently and through their interaction with IL-6, by taking advantage of the high fibrinogen and IL-6 concentrations and the low linkage disequilibrium (LD) reported in black South Africans
When investigating the effect of fibrinogen genetics on fibrinogen concentrations and cardiovascular disease (CVD) outcome, the possible interactions with modulating factors and the fact that single nucleotide polymorphisms (SNPs) effects seem to be additive should be taken into account
Summary
Fibrinogen is central to blood coagulation and the inflammatory response. As a haemostatic protein, fibrinogen is activated by thrombin to form fibrin, the main constituent of a blood clot [1]. As an acute phase reactant, fibrinogen is up-regulated upon stimulation by inflammatory cytokines, primarily interleukin-6 (IL-6), in response to physiological trauma such as infection/inflammation [2]. Both fibrinogen and IL-6 are prospectively associated with cardiovascular disease (CVD) risk [3,4,5], causality is under debate [6,7,8,9]. Fibrinogen expression is regulated on two levels: under basal conditions and during the acute phase response [14, 15]. Sequences responsive to IL-6, and crucial for full IL-6-induced fibrinogen expression, have been identified upstream of the fibrinogen genes [14, 15]
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