A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance

Hepatology. 2015 Nov;62(5):1375-87. doi: 10.1002/hep.28105. Epub 2015 Sep 28.

Abstract

Patients carrying very rare loss-of-function mutations in interleukin-1 receptor-associated kinase 4 (IRAK4), a critical signaling mediator in Toll-like receptor signaling, are severely immunodeficient, highlighting the paramount role of IRAK kinases in innate immunity. We discovered a comparatively frequent coding variant of the enigmatic human IRAK2, L392V (rs3844283), which is found homozygously in ∼15% of Caucasians, to be associated with a reduced ability to induce interferon-alpha in primary human plasmacytoid dendritic cells in response to hepatitis C virus (HCV). Cytokine production in response to purified Toll-like receptor agonists was also impaired. Additionally, rs3844283 was epidemiologically associated with a chronic course of HCV infection in two independent HCV cohorts and emerged as an independent predictor of chronic HCV disease. Mechanistically, IRAK2 L392V showed intact binding to, but impaired ubiquitination of, tumor necrosis factor receptor-associated factor 6, a vital step in signal transduction.

Conclusion: Our study highlights IRAK2 and its genetic variants as critical factors and potentially novel biomarkers for human antiviral innate immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Genotype
  • HEK293 Cells
  • Hepatitis C, Chronic / immunology*
  • Humans
  • Interferon-alpha / biosynthesis
  • Interferons
  • Interleukin-1 Receptor-Associated Kinases / genetics*
  • Interleukin-1 Receptor-Associated Kinases / physiology
  • Interleukins / genetics
  • Polymorphism, Single Nucleotide
  • TNF Receptor-Associated Factor 6 / metabolism
  • Toll-Like Receptors / physiology
  • Ubiquitination

Substances

  • IFNL3 protein, human
  • Interferon-alpha
  • Interleukins
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptors
  • Interferons
  • Interleukin-1 Receptor-Associated Kinases