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IFNL3

HGNC:18365 19q13.13

Friday 11 January 2013

IL28B, "interleukin 28B", "interleukin 28B (interferon, lambda 3)"; interferon, lambda 3

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.