IFNL3

Pathology

 A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. (doi:10.1038/ng.2521 )

• Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer.
• RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection discovered upstream of IFNL3 (IL28B) on chromosome 19q13.13 a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance.
• ss469415590[ΔG] is a frameshift variant that creates a novel gene, designated IFNL4, encoding the interferon-λ4 protein (IFNL4), which is moderately similar to IFNL3.
• Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians.
• Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes.
• This findings provide new insights into the genetic regulation of HCV clearance and its clinical management.
• This study suggested natural clearance of hepatitis C virus is compromised in individuals with the frame-shift variant ss469415590, which falls upstream of the interleukin-28-coding gene IFNL3 (also called IL28B).
• It detected the suspicious variant through RNA sequencing and 5’ rapid amplification of cDNA ends, or RACE, experiments on human liver cells challenged with a synthetic compound that mimics HCV.
• The cell line was developed using samples from an uninfected individual who was heterozygous for rs12979860, an IFNL3/IL28B SNP tied to HCV clearance in past studies.
• Together, results of these and other analyses suggested that ss469415590 — which is found in linkage disequilibrium with rs12979860 — alters IFNL3/IL28B in ways that produce a substitute protein-coding gene called IFNL4.
• And though that protein appears to trigger some antiviral pathways in the cell, investigators said, it also coincides with an overall dip in HCV clearance.

 An independent team from Spain’s National Center for Microbiology verified ties between spontaneous HCV clearance and several different IL28B variants through a meta-analysis that brought together data from past studies involving up to 23,500 people. (doi:10.1186/1741-7015-11-6 )

• The impact of the pro-clearance SNPs varied somewhat depending on the population considered and the HCV genotype involved, the researchers noted.
• Results of that study also suggested that SNPs in IL28B may help in predicting who will respond most favorably to pegylated interferon-alpha plus ribavirin treatments for HCV infection.
• If such findings hold, study authors said that it eventually may be possible to guide HCV treatments in a more targeted manner, siphoning individuals with IL28B variants linked to poor PEG-IFN/RBV response off into alternative treatment strategy pools.
• Treatment with PEG-IFN/RBV is costly and can have side effects which prevent patient compliance. Consequently knowing a patient’s IL28B status will help target interferon treatment to those who will benefit most and play a substantial role in the selection of candidates for standard treatment versus triple therapy with direct-acting antivirals.