title: IFN-λ3, not IFN-λ4, likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis.
abstract: Genetic variation in the IFNL3-IFNL4 (interferon-λ3-interferon-λ4) region is associated with hepatic inflammation and fibrosis. Whether IFN-λ3 or IFN-λ4 protein drives this association is not known. We demonstrate that hepatic inflammation, fibrosis stage, fibrosis progression rate, hepatic infiltration of immune cells, IFN-λ3 expression, and serum sCD163 levels (a marker of activated macrophages) are greater in individuals with the IFNL3-IFNL4 risk haplotype that does not produce IFN-λ4, but produces IFN-λ3. No difference in these features was observed according to genotype at rs117648444, which encodes a substitution at position 70 of the IFN-λ4 protein and reduces IFN-λ4 activity, or between patients encoding functionally defective IFN-λ4 (IFN-λ4-Ser70) and those encoding fully active IFN-λ4-Pro70. The two proposed functional variants (rs368234815 and rs4803217) were not superior to the discovery SNP rs12979860 with respect to liver inflammation or fibrosis phenotype. IFN-λ3 rather than IFN-λ4 likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis.
authors.affiliation: Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Eslam
authors.affiliation: Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, New South Wales, Australia.
authors.forename: Duncan
authors.initials: D
authors.lastname: McLeod
authors.affiliation: Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Kebitsaone Simon
authors.initials: KS
authors.lastname: Kelaeng
authors.affiliation: Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mangia
authors.affiliation: Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.affiliation: Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia.|Biochemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt.
authors.forename: Khaled
authors.initials: K
authors.lastname: Thabet
authors.affiliation: NIHR Biomedical Research Unit in Gastroenterology and the Liver, University of Nottingham, Nottingham, UK.
authors.forename: William L
authors.initials: WL
authors.lastname: Irving
authors.affiliation: Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Dore
authors.affiliation: Institute of Translational and Stratified Medicine, Plymouth University, Plymouth, UK.
authors.forename: David
authors.initials: D
authors.lastname: Sheridan
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Henning
authors.initials: H
authors.lastname: Grønbæk
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy.
authors.forename: Maria Lorena
authors.initials: ML
authors.lastname: Abate
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors.forename: Rune
authors.identifier: http://orcid.org/0000-0003-1159-066X
authors.initials: R
authors.lastname: Hartmann
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bugianesi
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
authors.affiliation: UCM IC Digestive Diseases and ciberehd. University Hospital Virgen del Rocio, Institute of Biomedicine of Seville, Seville, Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Rojas
authors.affiliation: Institute of Immunology and Allergy Research, Westmead Hospital and Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Booth
authors.affiliation: Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, New South Wales, Australia.
authors.forename: Martin
authors.initials: M
authors.lastname: Weltman
authors.affiliation: Department of Gastroenterology and Hepatology, Fremantle Hospital, Fremantle, Western Australia, Australia.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Mollison
authors.affiliation: Department of Gastroenterology and Hepatology, Royal Perth Hospital, Perth, Western Australia, Australia.
authors.forename: Wendy
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Riordan
authors.affiliation: Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, New South Wales, Australia.
authors.forename: Hema
authors.initials: H
authors.lastname: Mahajan
authors.affiliation: Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany.
authors.forename: Janett
authors.initials: J
authors.lastname: Fischer
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Jacob
authors.initials: J
authors.lastname: Nattermann
authors.affiliation: Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia.|Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, New South Wales, Australia.
authors.forename: Mark W
authors.identifier: http://orcid.org/0000-0003-4621-3485
authors.initials: MW
authors.lastname: Douglas
authors.affiliation: Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.affiliation: University of Queensland, School of Medicine, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Powell
authors.affiliation: UCM IC Digestive Diseases and ciberehd. University Hospital Virgen del Rocio, Institute of Biomedicine of Seville, Seville, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Romero-Gomez
authors.affiliation: Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Jacob
authors.initials: J
authors.lastname: George
mesh_terms: D005355:Fibrosis / Q000235:genetics / Q000378:metabolism; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D016174:Hepacivirus / Q000502:physiology; D006526:Hepatitis C / Q000235:genetics / Q000821:virology; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D007372:Interferons; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D015810:Linkage Disequilibrium; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D016015:Logistic Models; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000095022:Interferon Lambda
chemical_list: D007372:Interferons; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579163:IFNL4 protein, human