Functional genetic variants of the IFN-λ3 (IL28B) gene and transcription factor interactions on its promoter

Abstract

Interferon lambda 3 (IFN-λ3 or IFNL3, formerly IL28B), a type III interferon, modulates immune responses during infection/inflammation. Several human studies have reported an association of single nucleotide polymorphisms (SNP) in the IFNL3 locus with expression level of IFNL3. Previous genetic studies, in the context of hepatitis C virus infections, had predicted three regulatory SNPs: rs4803219, rs28416813 and rs4803217 that could have functional/causal roles. Subsequent studies confirmed this prediction for rs28416813 and rs4803217. A dinucleotide TA-repeat variant (rs72258881) has also been reported to be regulating the IFN-λ3 promoter. In this study, we tested all these genetic variants using a sensitive reporter assay. We show that the minor/ancestral alleles of both rs28416813 and rs4803217, together have a strong inhibitory effect on reporter gene expression. We also show an interaction between the two principal transcription factors regulating IFNL3 promoter: IRF7 and NF-kB RelA/p65. We show that IRF7 and p65 physically interact with each other. By using a transient ChIP assay, we show that presence of p65 increases the promoter occupancy of IRF7, thereby leading to synergistic activation of the IFNL3 promoter. We reason that, in contrast to p65, a unique nature of IRF7 binding to its specific DNA sequence makes it more sensitive to changes in DNA phasing. As a result, we see that IRF7, but not p65-mediated transcriptional activity is affected by the phase changes introduced by the TA-repeat polymorphism. Overall, we see that three genetic variants: rs28416813, rs4803217 and rs72258881 could have functional roles in controlling IFNL3 gene expression.

Favorable Genotypes of Type III Interferon Confer Risk of Dyslipidemia in the Population With Obesity

“…Many studies have identified IFNL3 polymorphisms to be correlated with the outcome of hepatitis-C infection. Scholars have found that major alleles and favorable genotypes lead to higher expression of IFNL3 , better response to therapy, and viral clearance in patients ( 36 – 42 ). Unlike other research limited to infectious diseases, we investigated people with obesity.…”

Experimental Research on the Inhibitory Effect of IFN-Lambda 3 Combined with Sorafenib on the Growth of Liver Cancer Transplanted into Nude Mice

“…Recent research has supplemented the member composition of type III IFN family, which is known as IFN-lambda 4. However, at present, there is more inclination to research about the functions related to IFN-Lambda 3 [14] . Previous studies have shown that IFN-alpha and sorafenib have antitumor effects on HCC in vitro and in vivo [15] .…”

Gender‐dependent multiple cross‐phenotype association of interferon lambda genetic variants with peripheral blood profiles in healthy individuals

“…The IFNL locus has been under strong selective pressure during human evolution (Manry et al, 2011). Genetic variants have been identified that control the expression of IFN‐λ3 (rs28416813 and rs4803217) (Chinnaswamy et al, 2013; McFarland et al, 2014; Roy et al, 2021) and expression and activity of IFN‐λ4 (rs368234815 and rs117648444, respectively) (Prokunina‐Olsson et al, 2013; Terczyńska‐Dyla et al, 2014) (Figure 1a). These variants have been associated with several infectious and inflammatory diseases, including COVID‐19 (Chinnaswamy, 2016; Matic et al, 2023; Prokunina‐Olsson, 2019).…”

“…The SNP (single nucleotide polymorphism) rs117648444 (G/A) is a non‐synonymous variant that changes the amino acid at 70th position in IFN‐λ4 from proline to serine (P70 or S70); the S70 variant has significantly reduced activity in terms of levels of IFN‐stimulated gene (ISG) expression compared to P70 in vitro and it phenocopies the TT allele that abolishes the expression of an active IFN‐λ4 due to disruption of the ORF, in association with tests involving HCV treatment response cohorts (Bhushan et al, 2017; Terczyńska‐Dyla et al, 2014). The SNPs rs28416813 (C/G) and rs4803217 (C/A) present in the 5′UTR and 3′UTR, respectively, of the IFNL3 gene potentially regulate the expression levels of IFN‐λ3 (Chinnaswamy et al, 2013; McFarland et al, 2014; Roy et al, 2021). The SNP rs12979860 (C/T) was the strongest signal in the HCV GWAS and is usually included as a proxy SNP for IFNL gene functional variants (Ge et al, 2009; Prokunina‐Olsson, 2019).…”