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Sci Rep. 2019 Feb 5;9(1):1439. doi: 10.1038/s41598-018-35736-2.

A variant in the MICA gene is associated with liver fibrosis progression in chronic hepatitis C through TGF-β1 dependent mechanisms.

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Storr Liver Centre, The Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, and Westmead Hospital NSW, Sydney, Australia.
Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy.
Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany.
Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario Virgen del Rocío, University of Seville, Sevilla, Spain.
Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy.
NIHR Biomedical Research Unit in Gastroenterology and the Liver, University of Nottingham, Nottingham, United Kingdom.
Institute of Translational and Stratified Medicine, Plymouth University, Plymouth, United Kingdom.
Kirby Institute, The University of New South Wales, Sydney, NSW, Australia.
Department of Internal Medicine I, University of Bonn, Bonn, Germany.
Università degli Studi di Milano Centro A.M. e A. Migliavacca, First Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation Milan Italy, Milan, Italy.
Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, NSW, Australia.
Department of Gastroenterology and Hepatology, Fremantle Hospital, Fremantle, WA, Australia.
Department of Gastroenterology & Hepatology, Royal Perth Hospital, Wellington, WA, Australia.
Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, NSW, Australia.
Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, Australia.
The University of Queensland, School of Medicine, Princess Alexandra Hospital, Woolloongabba, QLD, Australia.
Biochemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt.
Department of Medical Laboratories Technology, Faculty of Applied Medical Sciences, Taibah University, Medina, Saudi Arabia.
Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, NSW, Australia.
Storr Liver Centre, The Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, and Westmead Hospital NSW, Sydney, Australia.


Hepatocarcinogenesis is tightly linked to liver fibrosis. Recently, two GWAS variants, MICA rs2596542 and DEPDC5 rs1012068 were identified as being associated with the development of HCV-induced hepatocellular carcinoma (HCC) in Japanese patients. The role of these variants on hepatic inflammation and fibrosis that are closely associated with HCC development is not known, nor are the biological mechanisms underlying their impact on the liver. Here, we demonstrate in 1689 patients with chronic hepatitis C (CHC) (1,501 with CHC and 188 with HCV-related HCC), that the MICA (T) allele, despite not being associated with HCC susceptibility, is associated with increased fibrosis stage (OR: 1.47, 95% CI: 1.05-2.06, p = 0.02) and fibrosis progression rate (hazards ratio: 1.41, 95% CI: 1.04-1.90, p = 0.02). The DEPDC5 variant was not associated with any of these phenotypes. MICA expression was down-regulated in advanced fibrosis stages. Further, (T) allele carriage was associated with lower MICA expression in liver and serum. Transforming growth factor-β1 (TGF-β1) expression suppresses MICA expression in hepatic stellate cells. Our findings suggest a novel mechanism linking susceptibility to advanced fibrosis and subsequently indirectly to HCC, to the level of MICA expression through TGF-β1-dependent mechanisms.

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