A Single Nucleotide Polymorphism Associated with Hepatitis C Virus Infections Located in the Distal Region of the IL28B Promoter Influences NF-κB-Mediated Gene Transcription

Abstract

Persistence of hepatitis C virus (HCV) infection is observed only in a subset of infected individuals and among them only some respond to treatment. Genome-wide association studies (GWAS) carried out around the world identified single nucleotide polymorphisms (SNPs) in the IL28B locus that are strongly associated with both HCV clearance and treatment response. The functional significance of these associations however, is not clear. In this report we show that an SNP rs28416813 in the distal promoter region of IL28B that is in close proximity to a non-consensus NF-κB-binding site affects downstream reporter gene expression. The effect is likely due to differential binding of NF-κB at the non-consensus site. The non-protective allele showed a reduction in luciferase reporter gene expression compared to the protective allele in HEK293T cells under different experimental conditions including treatment with tumor necrosis factor alpha (TNF-α) and 5′ triphosphorylated dsRNA. Furthermore, the HCV RNA polymerase was able to induce transcription from the IL28B promoter in a RIG-I-dependent manner. This induction was influenced by the alleles present at rs28416813. We also demonstrate strong linkage disequilibrium between rs28416813 and another important SNP rs12979860 in two ethnic populations. These results suggest possible mechanisms by which SNPs at the IL28B locus influence spontaneous clearance and treatment response in chronic HCV infections.

The correlation between pretreatment cytokine expression patterns in peripheral blood mononuclear cells with chronic hepatitis c outcome

“…Various pro- and anti-inflammatory factors and virus inhibiting immune system components such as cytokines and their receptors, were subject of a number of studies. Most attention was devoted to TNF-α, IFN-γ, IL-6, IL-8, IL-10 [ 8 – 13 ], however, many other cytokines [ 14 – 16 ] as well as transcription factors [ 17 , 18 ] were also analyzed. A limited number of studies addressed the issue whether pretreatment levels of cytokines are predictive of outcome.…”

Interferon Lambda: Modulating Immunity in Infectious Diseases

“…Expression of IFN-λ ligands is modulated by SNPs in both transcription factor binding sites and methylation sites of the promoter region, as well as frameshift mutations (99)(100)(101)(102). The IFN-λ gene layout is shown in Figure 2.…”

Impact of host genetic polymorphisms on vaccine induced antibody response

“…63,64 Since 2009, SNPs in IFNL3/4 genes are associated with the HCV treatment outcome. 60,61,[65][66][67][68][69][70] In particular, SNPs in IFNL3 (rs8099917) and IFNL4 (rs368234815) have been proposed as predictors for spontaneous viral clearance and treatment success to pegylated interferon a/ribavirin (PEG-IFN-a/RBV) treatment. 60,61 The IFNL4 SNP (rs368234815) has also been associated with CMV retinitis in HIV-infected risk patients (nD1134, p-valueD7E-3), 71 as well as with CMV replication in solid-organ transplant recipients at risk (nD455, p-valueD4E-02).…”