IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction

J Exp Med. 2013 Jun 3;210(6):1109-16. doi: 10.1084/jem.20130012. Epub 2013 May 27.

Abstract

Approximately 3% of the world population is chronically infected with the hepatitis C virus (HCV), with potential development of cirrhosis and hepatocellular carcinoma. Despite the availability of new antiviral agents, treatment remains suboptimal. Genome-wide association studies (GWAS) identified rs12979860, a polymorphism nearby IL28B, as an important predictor of HCV clearance. We report the identification of a novel TT/-G polymorphism in the CpG region upstream of IL28B, which is a better predictor of HCV clearance than rs12979860. By using peripheral blood mononuclear cells (PBMCs) from individuals carrying different allelic combinations of the TT/-G and rs12979860 polymorphisms, we show that induction of IL28B and IFN-γ-inducible protein 10 (IP-10) mRNA relies on TT/-G, but not rs12979860, making TT/-G the only functional variant identified so far. This novel step in understanding the genetic regulation of IL28B may have important implications for clinical practice, as the use of TT/G genotyping instead of rs12979860 would improve patient management.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Chemokine CXCL10 / biosynthesis
  • Chemokine CXCL10 / genetics
  • Chemokine CXCL10 / immunology
  • Genotype
  • Hepacivirus / physiology*
  • Hepatitis C, Chronic / genetics*
  • Hepatitis C, Chronic / immunology
  • Hepatitis C, Chronic / virology*
  • Humans
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Interferons
  • Interleukins / biosynthesis*
  • Interleukins / genetics
  • Interleukins / immunology
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / virology
  • Polymorphism, Genetic
  • RNA, Messenger / genetics

Substances

  • CXCL10 protein, human
  • Chemokine CXCL10
  • IFNL3 protein, human
  • Interleukins
  • RNA, Messenger
  • Interferon-gamma
  • Interferons