7 research outputs found
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
Pairwise LD structure of 14 fibrinogen SNPs, illustrated by D’ values on an r<sup>2</sup> colour scheme.
<p>Empty boxes indicate D’ values of 1.0. Increased numerical values indicate stronger evidence of LD. Image generated through Haploview software [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0187712#pone.0187712.ref051" target="_blank">51</a>].</p
Association of selected upstream <i>FGB</i> polymorphisms with fibrinogen-related phenotypes.
<p>Association of selected upstream <i>FGB</i> polymorphisms with fibrinogen-related phenotypes.</p
Genotype-IL-6 interactions modulating clot properties.
<p>Genotype-IL-6 interactions modulating clot properties.</p
Genotype-IL-6 interactions modulating total fibrinogen concentrations.
<p>Genotype-IL-6 interactions modulating total fibrinogen concentrations.</p
Fourteen polymorphisms spanning the fibrinogen gene cluster.
<p>Image generated through the Ensembl database [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0187712#pone.0187712.ref050" target="_blank">50</a>].</p
Association of total fibrinogen concentrations with circulating interleukin-6 by risk score groups.
<p>Association of total fibrinogen concentrations with circulating interleukin-6 by risk score groups.</p