Interferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease

Mohammed Eslam; Ahmed M Hashem; Reynold Leung; Manuel Romero-Gomez; Thomas Berg; Gregory J Dore; Henry L K Chan; William L Irving; David Sheridan; Maria L Abate; Leon A Adams; Alessandra Mangia; Martin Weltman; Elisabetta Bugianesi; Ulrich Spengler; Olfat Shaker; Janett Fischer; Lindsay Mollison; Wendy Cheng; Elizabeth Powell; Jacob Nattermann; Stephen Riordan; Duncan McLeod; Nicola J Armstrong; Mark W Douglas; Christopher Liddle; David R Booth; Jacob George; Golo Ahlenstiel; International Hepatitis C Genetics Consortium (IHCGC)

doi:10.1038/ncomms7422

Interferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease

Nat Commun. 2015 Mar 5:6:6422. doi: 10.1038/ncomms7422.

Authors

Mohammed Eslam¹, Ahmed M Hashem², Reynold Leung³, Manuel Romero-Gomez⁴, Thomas Berg⁵, Gregory J Dore⁶, Henry L K Chan⁷, William L Irving⁸, David Sheridan⁹, Maria L Abate¹⁰, Leon A Adams¹¹, Alessandra Mangia¹², Martin Weltman¹³, Elisabetta Bugianesi¹⁰, Ulrich Spengler¹⁴, Olfat Shaker¹⁵, Janett Fischer¹⁶, Lindsay Mollison¹⁷, Wendy Cheng¹⁸, Elizabeth Powell¹⁹, Jacob Nattermann¹⁴, Stephen Riordan²⁰, Duncan McLeod²¹, Nicola J Armstrong²², Mark W Douglas¹, Christopher Liddle¹, David R Booth²³, Jacob George¹, Golo Ahlenstiel¹; International Hepatitis C Genetics Consortium (IHCGC)

Collaborators

International Hepatitis C Genetics Consortium (IHCGC):
Javier Ampuero⁴, Margaret Bassendine²⁴, Vincent W S Wong⁷, Chiara Rosso¹⁰, Rose White¹, Lavinia Mezzabotta¹⁰, Vijayaprakash Suppiah¹, Monika Michalk¹⁴, Barbara Malik¹⁶, Gail Matthews²⁵, Tanya Applegate²⁶, Jason Grebely²⁶, Vincenzo Fragomeli¹³, Julie R Jonsson²⁷, Rosanna Santaro¹²

Affiliations

¹ Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia.
² Faculty of Engineering, Department of Systems and Biomedical Engineering, Minia University, Minia 6111, Egypt.
³ 1] Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia [2] Institute of Immunology and Allergy Research, Westmead Hospital and Westmead Millennium Institute, University of Sydney, Sydney, New South Wales 2145, Australia.
⁴ Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Sevilla 41014, Spain.
⁵ 1] Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charite, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin 04103, Germany [2] Department of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig 04103, Germany.
⁶ 1] Kirby Institute, The University of New South Wales, Sydney, New South Wales 2052, Australia [2] St Vincent's Hospital, Sydney, New South Wales 2052, Australia.
⁷ Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
⁸ NIHR Biomedical Research Unit in Gastroenterology and the Liver, University of Nottingham, Nottingham NG7 2UH, UK.
⁹ 1] Liver Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK [2] Institute of Translational and Stratified Medicine, Plymouth University, Plymouth PL4 8AA, UK.
¹⁰ Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin 10126, Italy.
¹¹ School of Medicine and Pharmacology, Sir Charles Gairdner Hospital Unit, University of Western Australia, Nedlands, Western Australia 6009, Australia.
¹² Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo 71013, Italy.
¹³ Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, New South Wales 2747, Australia.
¹⁴ Department of Internal Medicine I, University of Bonn, Bonn 53105, Germany.
¹⁵ Faculty of Medicine, Medical Biochemistry and Molecular Biology Department, Cairo University, Cairo 11562, Egypt.
¹⁶ Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charite, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin 04103, Germany.
¹⁷ Department of Gastroenterology and Hepatology, Fremantle Hospital, Fremantle, Western Australia 6160, Australia.
¹⁸ Department of Gastroenterology and Hepatology, Royal Perth Hospital, Perth, Western Australia 6000, Australia.
¹⁹ 1] Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia [2] The University of Queensland, School of Medicine, Princess Alexandra Hospital, Woolloongabba, Queensland 4072, Australia.
²⁰ Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, New South Wales 2031, Australia.
²¹ Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, New South Wales 2145, Australia.
²² School of Mathematics and Statistics, University of Sydney, Sydney, New South Wales 2006, Australia.
²³ Institute of Immunology and Allergy Research, Westmead Hospital and Westmead Millennium Institute, University of Sydney, Sydney, New South Wales 2145, Australia.
²⁴ Liver Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
²⁵ Kirby Institute, The University of New South Wales, Sydney, New South Wales 2052, Australia.
²⁶ The Kirby Institute, University of New South Wales, Sydney, New South Wales 2033, Australia.
²⁷ Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia.

Abstract

Tissue fibrosis is a core pathologic process that contributes to mortality in ~45% of the population and is likely to be influenced by the host genetic architecture. Here we demonstrate, using liver disease as a model, that a single-nucleotide polymorphism (rs12979860) in the intronic region of interferon-λ4 (IFNL4) is a strong predictor of fibrosis in an aetiology-independent manner. In a cohort of 4,172 patients, including 3,129 with chronic hepatitis C (CHC), 555 with chronic hepatitis B (CHB) and 488 with non-alcoholic fatty liver disease (NAFLD), those with rs12979860CC have greater hepatic inflammation and fibrosis. In CHC, those with rs12979860CC also have greater stage-constant and stage-specific fibrosis progression rates (P<0.0001 for all). The impact of rs12979860 genotypes on fibrosis is maximal in young females, especially those with HCV genotype 3. These findings establish rs12979860 genotype as a strong aetiology-independent predictor of tissue inflammation and fibrosis.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Cohort Studies
Female
Genotype
Hepatitis, Chronic / complications*
Humans
Interleukins / genetics*
Liver / pathology
Liver Cirrhosis / complications
Liver Cirrhosis / genetics
Liver Cirrhosis / pathology*
Logistic Models
Non-alcoholic Fatty Liver Disease / complications*
Polymorphism, Single Nucleotide / genetics*
Sex Factors
Statistics, Nonparametric

Substances

IFNL4 protein, human
Interleukins