title: Hepatic metallothionein expression in chronic hepatitis C virus infection is IFNL3 genotype-dependent.
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.
authors: Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors: K S
authors: KS
authors: O'Connor
authors: Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors: G
authors: G
authors: Parnell
authors: Department of Mathematics, University of Sydney, Sydney, New South Wales, Australia.
authors: E
authors: E
authors: Patrick
authors: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia.
authors: G
authors: G
authors: Ahlenstiel
authors: 1] Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia [2] Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia.
authors: V
authors: V
authors: Suppiah
authors: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia.
authors: D
authors: D
authors: van der Poorten
authors: 1] Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia [2] Centre for Infectious Diseases and Microbiology, Sydney Emerging infections and Biosecurity Institute, University of Sydney and Westmead Hospital, Sydney, New South Wales, Australia.
authors: S A
authors: SA
authors: Read
authors: 1] Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia [2] Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia.
authors: R
authors: R
authors: Leung
authors: 1] Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia [2] Centre for Infectious Diseases and Microbiology, Sydney Emerging infections and Biosecurity Institute, University of Sydney and Westmead Hospital, Sydney, New South Wales, Australia.
authors: M W
authors: MW
authors: Douglas
authors: Department of Mathematics, University of Sydney, Sydney, New South Wales, Australia.
authors: J Y H
authors: JY
authors: Yang
authors: Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors: G J
authors: GJ
authors: Stewart
authors: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia.
authors: C
authors: C
authors: Liddle
authors: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia.
authors: J
authors: J
authors: George
authors: Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors: D R
authors: DR
authors: Booth
mesh_terms: D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics; D016898:Interferon-alpha / Q000627:therapeutic use; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008099:Liver / Q000473:pathology / Q000821:virology; D008103:Liver Cirrhosis / Q000235:genetics; D008668:Metallothionein / Q000096:biosynthesis*; D011092:Polyethylene Glycols / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D016896:Treatment Outcome; D015854:Up-Regulation; D019562:Viral Load / Q000235:genetics*; D000095022:Interferon Lambda
chemical_list: D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D008668:Metallothionein; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C100416:peginterferon alfa-2a