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

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

Author information

1
Junior Research Group Toll-Like Receptors and Cancer, German Cancer Research Center, Heidelberg, Germany.
2
Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.
3
Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany.
4
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.
5
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
6
NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.
7
Department of General, Visceral, and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.
8
Gastroenterology and Hepatology Department, University Hospital Zurich, Zurich, Switzerland.
9
Department of Gastroenterology and Hepatology, Canton Hospital St. Gallen, St. Gallen, Switzerland.
10
Hepatology Section, Department Visceral Surgery and Medicine, University Hospital Bern, Bern, Switzerland.
11
Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

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.

PMID:
26250868
DOI:
10.1002/hep.28105
[Indexed for MEDLINE]

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