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

Text A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance..pdf - Published Version Restricted to registered users only Available under License Publisher holds Copyright. Download (744kB)

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.

Interest & Impact

Downloads

2 since deposited on 31 Mar 2016
0 in the past 12 months

Citations

5 Citations in Web of Science ®
6 Citations in Scopus

Search

in Google Scholar™

Services

Actions (login required)

Edit item

Actions (login required)

Edit item