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Review
. 2019 Oct;39(10):618-626.
doi: 10.1089/jir.2019.0048. Epub 2019 Jun 4.

What Have We Learned from Studies of IFN-λ Variants and Hepatitis C Virus Infection?

Thomas R O'Brien  1 , Sarah S Jackson  1
Affiliations
Review

What Have We Learned from Studies of IFN-λ Variants and Hepatitis C Virus Infection?

Thomas R O'Brien et al. J Interferon Cytokine Res. 2019 Oct.

Abstract

Chronic infection with the hepatitis C virus (HCV) is a major cause of cirrhosis and hepatocellular carcinoma. In 2009, genome-wide association studies (GWAS) strongly linked genetic variants in the interferon lambda (IFN-λ) chromosomal region to HCV clearance. In 2013, discovery of the IFNL4 gene provided a functional explanation for those GWAS findings. The IFNL4-ΔG/TT (rs368234815) variant controls generation of the IFN-λ4 protein. Paradoxically, the IFNL4-TT allele, which abrogates IFN-λ4, associates with higher rates of spontaneous HCV clearance and better response to treatments for HCV infection. The finding that a "knock-out" allele for IFN-λ4 enhances HCV clearance challenges the paradigm of IFNs as antiviral cytokines. Genetic variants in the IFN-λ region have also been associated with hepatic inflammation and fibrosis from various etiologies, however, alleles that are linked with improved HCV clearance associates with worse inflammation and fibrosis. These studies demonstrate that GWAS of infectious diseases may yield important and unexpected biological insights.

Keywords: IFNL4; epidemiology; fibrosis; genetics; hepatocellular carcinoma; innate immunity; treatment response; viral clearance.

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Conflict of interest statement

No competing financial interests exist.

Figures

<b>FIG. 1.</b>
FIG. 1.
SNPs associated with response to peg-IFNα/ribavirin therapy and spontaneous clearance of HCV in GWAS (Ge and others ; Suppiah and others ; Tanaka and others 2009). rs12979860 lies within IFNL4 and rs8099917 lies nearer IFNL4 than IFNL3, therefore, these SNPs are properly termed variants of IFNL4, which was discovered subsequent to the GWAS reports (Prokunina-Olsson and others 2013). GWAS, genome-wide association studies; HCV, hepatitis C virus; IFN, interferon; SNP, single nucleotide polymorphism.
<b>FIG. 2.</b>
FIG. 2.
IFN-λ4 structure and genetic variants. The IFNL4-ΔG/TT variant (rs368234815), which controls generation of IFN-λ4, lies in exon 1; GWAS marker rs12979860 lies in intron 1; the IFNL4-P70S variant (rs117648444), which modifies IFN-λ4, lies in exon 2 (Prokunina-Olsson and others 2013).
<b>FIG. 3.</b>
FIG. 3.
Decline in HCV RNA levels in response to treatment with peg-IFNα/ribavirin among African American participants in the Virahep-C Trial. Genotype for IFNL4-ΔG/TT was a stronger predictor than that for GWAS marker IFNL4-rs12979860 (P = 0.015) (Prokunina-Olsson and others 2013).
See this image and copyright information in PMC

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