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Wang, Hui; El Maadidi, Souhayla; Fischer, Janett; Grabski, Elena; Dickhöfer, Sabine; Klimosch, Sascha; Flannery, Sinead M.; Filomena, Angela; Wolz, Olaf‐Oliver; Schneiderhan‐Marra, Nicole; Löffler, Markus W.; Wiese, Manfred; Pichulik, Tica; Müllhaupt, Beat; Semela, David; Dufour, Jean‐François; Bochud, Pierre‐Yves; Bowie, Andrew G.; Kalinke, Ulrich; Berg, Thomas; Weber, Alexander N.R.

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

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  • Media type: E-Article
  • Title: A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance
  • Contributor: Wang, Hui; El Maadidi, Souhayla; Fischer, Janett; Grabski, Elena; Dickhöfer, Sabine; Klimosch, Sascha; Flannery, Sinead M.; Filomena, Angela; Wolz, Olaf‐Oliver; Schneiderhan‐Marra, Nicole; Löffler, Markus W.; Wiese, Manfred; Pichulik, Tica; Müllhaupt, Beat; Semela, David; Dufour, Jean‐François; Bochud, Pierre‐Yves; Bowie, Andrew G.; Kalinke, Ulrich; Berg, Thomas; Weber, Alexander N.R.
  • imprint: Ovid Technologies (Wolters Kluwer Health), 2015
  • Published in: Hepatology
  • Language: English
  • DOI: 10.1002/hep.28105
  • ISSN: 0270-9139; 1527-3350
  • Keywords: Hepatology
  • Origination:
  • Footnote:
  • Description: <jats:p>Patients carrying very rare loss‐of‐function mutations in interleukin‐1 receptor–associated kinase 4 (<jats:italic toggle="yes">IRAK4</jats:italic>), 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 <jats:italic toggle="yes">IRAK2</jats:italic>, 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. <jats:italic toggle="yes">Conclusion</jats:italic>: Our study highlights <jats:italic toggle="yes">IRAK2</jats:italic> and its genetic variants as critical factors and potentially novel biomarkers for human antiviral innate immunity. (H<jats:sc>epatology</jats:sc> 2015;62:1375–1387)</jats:p>
  • Access State: Open Access