Complement factor H gene (CFH) polymorphisms C-257T, G257A and haplotypes are associated with protection against severe dengue phenotype, possible related with high CFH expression

Abstract

Four genetic polymorphisms located at the promoter (C-257T) and coding regions of CFH gene (exon 2 G257A, exon 14 A2089G and exon 19 G2881T) were investigated in 121 dengue patients (DENV-3) in order to assess the relationship between allele/haplotypes variants and clinical outcomes. A statistical value was found between the CFH-257T allele (TT/TC genotypes) and reduced susceptibility to severe dengue (SD). Statistical associations indicate that individuals bearing a T allele presented significantly higher protein levels in plasma. The –257T variant is located within a NF-κB binding site, suggesting that this variant might have effect on the ability of the CFH gene to respond to signals via the NF-κB pathway. The G257A allelic variant showed significant protection against severe dengue. When CFH haplotypes effect was considered, the ancestral CG/CG promoter-exon 2 SNP genotype showed significant risk to SD either in a general comparison (ancestral × all variant genotypes), as well as in individual genotypes comparison (ancestral × each variant genotype), where the most prevalent effect was observed in the CG/CG × CA/TG comparison. These findings support the involvement of –257T, 257A allele variants and haplotypes on severe dengue phenotype protection, related with high basal CFH expression.

Emerging Concepts in Dengue Pathogenesis: Interplay between Plasmablasts, Platelets, and Complement in Triggering Vasculopathy

“…1). 46 A genetic polymorphism in factor H gene is associated with increased basal protein levels and is protective against severe dengue, 59 consistent with a role for loss of this regulatory pathway in disease pathogenesis. In addition to alternative pathway activation, MBL can bind to envelope protein of DENV 60 and thus could trigger the lectin pathway of complement activation during infection (Fig.…”

Cadmium Induces Glomerular Endothelial Cell–Specific Expression of Complement Factor H via the −1635 AP-1 Binding Site

“…Our study suggests distinct regulatory mechanisms of human and murine CFH transcription, although both of them might be induced by activation of the JNK pathway. As polymorphic variations in the CFH promoter have been shown to change CFH gene expression (49), it is possible that polymorphisms existing in the 21635 AP1 motif influence gene expression in humans.…”

Genetic variations of complement factor H and C3 in patients with thrombotic thrombocytopenic purpura (TTP) in northwest of Iran

“…This SNP is located at -257 upstream in the CFH promoter. Locating between glucocorticoid and nuclear factor-kappa B (NF-κB) binding sites makes it possible for the CFH gene SNP to respond to signals via the NF-κB pathway (19). The link between the T variant of the polymorphism rs3753394 and susceptibility to developing the aHUS (5,20), dengue fever (19), and AMD (21) have been reported.…”

“…Locating between glucocorticoid and nuclear factor-kappa B (NF-κB) binding sites makes it possible for the CFH gene SNP to respond to signals via the NF-κB pathway (19). The link between the T variant of the polymorphism rs3753394 and susceptibility to developing the aHUS (5,20), dengue fever (19), and AMD (21) have been reported. In a comprehensive analysis by Caprioli et al, on the gene polymorphism in 101 HUS patients, 32 TTP patients, and 106 healthy subjects, TTP group showed no mutation in CFHR1 or CFH (5).…”