Fibrinogen and clot-related phenotypes determined by fibrinogen polymorphisms: Independent and IL-6-interactive associations

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.白细胞介素-6（Interleukin-6, IL-6）可诱导纤维蛋白原（fibrinogen）的表达，而纤维蛋白原基因内的多态性变异被认为会改变该表达的幅度。此前欧洲人群纤维蛋白原基因座存在高度连锁不平衡（linkage disequilibrium, LD）的现象，这阻碍了对单个纤维蛋白原单核苷酸多态性（single nucleotide polymorphisms, SNPs）功能相关性的鉴定。本研究在2010年招募的、已知连锁不平衡程度较低的茨瓦纳（Tswana）人群中，对2个新型及12个具备潜在功能相关性的已知纤维蛋白原SNPs展开了分析。研究旨在依托南非黑人人群中较高的纤维蛋白原与IL-6浓度水平、以及较低的连锁不平衡特征，识别可独立影响凝血相关表型、总纤维蛋白原及γ’型纤维蛋白原浓度，或通过与IL-6的相互作用调控上述指标的功能性多态位点。研究结果显示，纤维蛋白原与IL-6存在显著关联，这介导了IL-6与凝血形成及结构的关联，但会削弱IL-6与凝血溶解时间的关联。本研究人群中未检出任何常见的欧洲人群纤维蛋白原样单倍型。潜在功能性纤维蛋白原SNPs FGB–rs7439150、rs1800789（–1420G/A）及rs1800787（–148C/T）与纤维蛋白原浓度及凝血特性改变存在显著关联，其中多项关联受IL-6浓度的显著调控。携带多个次要纤维蛋白原SNP等位基因对IL-6与纤维蛋白原浓度关联的影响呈累积效应：每多携带一个次要等位基因，IL-6与纤维蛋白原的关联强度便进一步增强。这一现象在凝血特性的差异中也得到了体现，提示其具备潜在临床相关性。因此，在探究纤维蛋白原遗传学特征对纤维蛋白原浓度及心血管疾病（Cardiovascular Disease, CVD）转归的影响时，应考虑其与调控因子间的潜在相互作用，以及SNP效应呈加性这一事实。