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

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; ... (2015). A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance. Hepatology, 62(5), pp. 1375-1387. Wiley Interscience 10.1002/hep.28105

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UNLABELLED 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology

UniBE Contributor:

Dufour, Jean-François

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0270-9139

Publisher:

Wiley Interscience

Language:

English

Submitter:

Lilian Karin Smith-Wirth

Date Deposited:

31 Mar 2016 17:37

Last Modified:

11 Sep 2017 18:59

Publisher DOI:

10.1002/hep.28105

PubMed ID:

26250868

BORIS DOI:

10.7892/boris.77721

URI:

https://boris.unibe.ch/id/eprint/77721

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