title: A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance.
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.
  
  
  CONCLUSIONS
  Our study highlights IRAK2 and its genetic variants as critical factors and potentially novel biomarkers for human antiviral innate immunity.
authors.affiliation: Junior Research Group Toll-Like Receptors and Cancer, German Cancer Research Center, Heidelberg, Germany.|Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.
authors.forename: Souhayla
authors.initials: S
authors.lastname: El Maadidi
authors.affiliation: Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.|Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Janett
authors.initials: J
authors.lastname: Fischer
authors.affiliation: Institute for Experimental Infection Research, TWINCORE Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Grabski
authors.affiliation: Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Dickhöfer
authors.affiliation: Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Klimosch
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Sinead M
authors.initials: SM
authors.lastname: Flannery
authors.affiliation: NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Filomena
authors.affiliation: Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.
authors.forename: Olaf-Oliver
authors.initials: OO
authors.lastname: Wolz
authors.affiliation: NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schneiderhan-Marra
authors.affiliation: Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.|Department of General, Visceral, and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Markus W
authors.initials: MW
authors.lastname: Löffler
authors.affiliation: Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Wiese
authors.affiliation: Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.
authors.forename: Tica
authors.initials: T
authors.lastname: Pichulik
authors.affiliation: Gastroenterology and Hepatology Department, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Müllhaupt
authors.affiliation: Department of Gastroenterology and Hepatology, Canton Hospital St. Gallen, St. Gallen, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Semela
authors.affiliation: Hepatology Section, Department Visceral Surgery and Medicine, University Hospital Bern, Bern, Switzerland.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
authors.affiliation: Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Bochud
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Bowie
authors.affiliation: Institute for Experimental Infection Research, TWINCORE Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.affiliation: Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.affiliation: Junior Research Group Toll-Like Receptors and Cancer, German Cancer Research Center, Heidelberg, Germany.|Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.
authors.forename: Alexander N R
authors.initials: AN
authors.lastname: Weber
mesh_terms: D005838:Genotype; D057809:HEK293 Cells; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis; D007372:Interferons; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics* / Q000502:physiology; D007378:Interleukins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000502:physiology; D054875:Ubiquitination; D000095022:Interferon Lambda
chemical_list: D016898:Interferon-alpha; D007372:Interferons; D053592:Interleukin-1 Receptor-Associated Kinases; D007378:Interleukins; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; C000624353:interferon-lambda, human; D000095022:Interferon Lambda