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Hepatic metallothionein expression in chronic hepatitis C virus infection is IFNL3 genotype-dependent

Genes & Immunity volume 15, pages 88–94 (2014)Cite this article

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Abstract

The IFNL3 genotype predicts the clearance of hepatitis C virus (HCV), spontaneously and with interferon (IFN)-based therapy. The responder genotype is associated with lower expression of interferon stimulated genes (ISGs) in liver biopsies from chronic hepatitis C patients. However, ISGs represent many interacting molecular pathways, and we hypothesised that the IFNL3 genotype may produce a characteristic pattern of ISG expression explaining the effect of genotype on viral clearance. For the first time, we identified an association between a cluster of ISGs, the metallothioneins (MTs) and IFNL3 genotype. Importantly, MTs were significantly upregulated (in contrast to most other ISGs) in HCV-infected liver biopsies of rs8099917 responders. An association between lower fibrosis scores and higher MT levels was demonstrated underlying clinical relevance of this association. As expected, overall ISGs were significantly downregulated in biopsies from subjects with the IFNL3 rs8099917 responder genotype (P=2.38 × 10−7). Peripheral blood analysis revealed paradoxical and not previously described findings with upregulation of ISGs seen in the responder genotype (P=1.00 × 10−4). The higher MT expression in responders may contribute to their improved viral clearance and MT-inducing agents may be useful adjuncts to therapy for HCV. Upregulation of immune cell ISGs in responders may also contribute to the IFNL3 genotype effect.

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Acknowledgements

KSO was supported by an Australian National Health and Medical Research Scholarship. Work on this manuscript was in part supported by research grants from the National Health and Medical Research Council of Australia (APP1006759) and by an Australian ARC linkage grant (LP0990067). JG is supported by the Robert W Storr bequest to the Sydney Medical Foundation, University of Sydney. DRB is supported by the Hunt Family Senior Research Fellowship.

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Authors and Affiliations

  1. Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia

    K S O'Connor, G Parnell, V Suppiah, R Leung, G J Stewart & D R Booth

  2. Department of Mathematics, University of Sydney, Sydney, New South Wales, Australia

    E Patrick & J YH Yang

  3. Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia

    G Ahlenstiel, V Suppiah, D van der Poorten, S A Read, R Leung, M W Douglas, C Liddle & J George

  4. Centre for Infectious Diseases and Microbiology, Sydney Emerging infections and Biosecurity Institute, University of Sydney and Westmead Hospital, Sydney, New South Wales, Australia

    S A Read & M W Douglas

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  1. K S O'Connor
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O'Connor, K., Parnell, G., Patrick, E. et al. Hepatic metallothionein expression in chronic hepatitis C virus infection is IFNL3 genotype-dependent. Genes Immun 15, 88–94 (2014). https://doi.org/10.1038/gene.2013.66

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