Multicenter Study

. 2015 Mar 5:6:6422.

doi: 10.1038/ncomms7422.

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

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, Affiliations

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.

PMID: 25740255
PMCID: PMC4366528
DOI: 10.1038/ncomms7422

Multicenter Study

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

Mohammed Eslam et al. Nat Commun. 2015.

. 2015 Mar 5:6:6422.

doi: 10.1038/ncomms7422.

Authors

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.

PMID: 25740255
PMCID: PMC4366528
DOI: 10.1038/ncomms7422

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.

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Figures

**Figure 1. IFNL genotype and hepatic inflammation and fibrosis.**
(a) rs12979860 genotype and hepatic inflammation degree in the cohort of patients with chronic hepatitis C (n=3,129). Pearson’s χ²-test and Fisher’s exact test were used to compare hepatic inflammation rates. (b) rs12979860 genotype and liver fibrosis stage in the cohort of patients with chronic hepatitis C (n=3,129). Pearson’s χ²-test and Fisher’s exact test were used to compare hepatic fibrosis rates. (c) Multivariate cox regressions analysis of rs12979860 genotype on the cumulative probability of progression to moderate/severe (≥F2) fibrosis after adjusting for covariates (age, gender, BMI, duration of the infection, HCV genotype, inflammation progression and basal ALT, AST, GGT, platelets, bilirubin and alkaline phosphatases) in 1,312 patients with an estimated duration of HCV infection. Bars indicate 95% CIs. (d) Stage-specific rates and 95% CIs of fibrosis progression according to rs12979860 genotype in 1,312 patients with an estimated duration of HCV infection. FPRs were obtained using the Markov maximum likelihood estimation. P-values were obtained using a likelihood ratio test comparing models with and without rs12979860 genotype. FPRs were significantly increased for the rs12979860 CC genotype compared with rs12979860 non-CC (P=0.0001). The influence of rs12979860 CC genotype was more important for early compared with late fibrosis stage transitions. Bars indicate 95% CIs.

**Figure 2. Interaction of rs12979860 with age and gender.**
(a) Multiple logistic regression analysis of rs12979860 genotype on the OR of having moderate/severe (≥F2) fibrosis stratified according to age and gender in the cohort of patients with chronic hepatitis C (n=3,129). Bars indicate 95% CIs. (b) Multivariate Cox regression analysis of rs12979860 genotype on the hazards of having moderate/severe (≥F2) fibrosis stratified according to age and gender in 1,312 patients with an estimated duration of HCV infection. Bars indicate 95% CIs.

**Figure 3. IFNL genotype and fibrosis in other non-CHC diseases.**
rs12979860 genotype and liver fibrosis in patients with (a) CHB (n=555) and (b) NAFLD (n=488). Pearson’s χ²-test and Fisher’s exact test were used to compare hepatic fibrosis rates.

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References

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources