Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study.

Autor:	Buch S; Department of Medicine I, Dresden University Hospital, Dresden, Germany Stephan.buch@uniklinikum-dresden.de.; Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany., Innes H; School of Health and Life Sciences, Glasgow Caledonian University School of Health and Life Sciences, Glasgow, UK.; NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK., Lutz PL; Department of Internal Medicine I, University of Bonn, Bonn, Germany., Nischalke HD; Department of Internal Medicine I, University of Bonn, Bonn, Germany., Marquardt JU; Department of Medicine I, University of Luebeck Human Medicine, Lubeck, Germany., Fischer J; Department of Gastroenterology and Rheumatology, Section Hepatology, Leipzig University, Leipzig, Germany., Weiss KH; Department of Internal Medicine, Krankenhaus Salem, Heidelberg, Germany., Rosendahl J; Department of Gastroenterology, University Hospital Halle, Halle, Germany., Marot A; Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.; Department of Gastroenterology and Hepatology, CHU UCL Namur, Université catholique de Louvain, Louvain-la-Neuve, Belgium., Krawczyk M; Department of Medicine II, Saarland University Medical Center, Saarland University, Saarbrucken, Germany.; Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warszawa, Poland., Casper M; Department of Medicine II, Saarland University Medical Center, Saarland University, Saarbrucken, Germany., Lammert F; Department of Medicine II, Saarland University Medical Center, Saarland University, Saarbrucken, Germany., Eyer F; Department of Clinical Toxicology, Klinikum Rechts der Isar, Technical University of Munich, Munchen, Germany., Vogel A; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany., Marhenke S; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany., von Felden J; Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Sharma R; Hammersmith Hospital Campus, Imperial College, London, UK., Atkinson SR; Hammersmith Hospital Campus, Imperial College, London, UK., McQuillin A; Molecular Psychiatry Laboratory, University College London, London, UK., Nattermann J; Department of Internal Medicine I, University of Bonn, Bonn, Germany., Schafmayer C; Department of General Surgery, Rostock University Medical Center, Rostock, Germany., Franke A; Institute for Clinical Molecular Biology, Kiel University, Kiel, Germany., Strassburg C; Department of Internal Medicine I, University of Bonn, Bonn, Germany., Rietschel M; Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany., Altmann H; Department of Medicine I, University Hospital Dresden, Dresden, Germany., Sulk S; Department of Medicine I, University Hospital Dresden, Dresden, Germany., Thangapandi VR; Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany.; Department of Medicine I, University Hospital Dresden, Dresden, Germany., Brosch M; Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany.; Department of Medicine I, University Hospital Dresden, Dresden, Germany., Lackner C; Institute of Pathology, University of Graz, Graz, Austria., Stauber RE; Department of Internal Medicine, University of Graz, Graz, Austria., Canbay A; Department of Internal Medicine, Ruhr-Universitat Bochum, Bochum, Germany., Link A; Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke Universitat Magdeburg, Magdeburg, Germany., Reiberger T; Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Wien, Austria., Mandorfer M; Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Wien, Austria., Semmler G; Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Wien, Austria., Scheiner B; Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Wien, Austria., Datz C; Department of Internal Medicine, General Hospital Oberndorf, Paracelsus Medical University Salzburg, Salzburg, Austria., Romeo S; Department of Molecular and Clinical Medicine, University of Gothenburg, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, Gothenburg, Sweden.; Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy., Ginanni Corradini S; Division of Gastroenterology, Department of Translational and Precision Medicine, University of Rome La Sapienza, Rome, Italy., Irving WL; Microbiology, University of Nottingham, Nottingham, UK., Morling JR; Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK., Guha IN; Nottingham Digestive Diseases NIHR Biomedical Research Unit, University Hospital, Nottingham, UK., Barnes E; Nuffield Department of Medicine, University of Oxford, Oxford, UK., Ansari MA; Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK., Quistrebert J; Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK., Valenti L; Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy., Müller SA; Department of Surgery, Hirslanden Klinik Beau-Site, Bern, Switzerland., Morgan MY; Division of Medicine, Royal Free Campus, UCL Institute for Liver and Digestive Health, London, UK., Dufour JF; Department of BioMedical Research, University of Bern, Bern, Switzerland., Trebicka J; Gastroenterology, Hepatology, Endocrinology and Clinical Infectiology, University of Münster, Münster, Germany., Berg T; Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig University, Leipzig, Germany., Deltenre P; Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.; Department of Gastroenterology and Hepatology, CHU UCL Namur, Université catholique de Louvain, Louvain-la-Neuve, Belgium., Mueller S; Salem Medical Center, Department of Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany., Hampe J; Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany.; Department of Medicine I, University Hospital Dresden, Dresden, Germany., Stickel F; Department of Gatroenterology and Hepatology, University of Zürich, Zürich, Switzerland.; Hirslanden Klinik Beau-Site, Bern, Switzerland.
Jazyk:	angličtina
Zdroj:	Gut [Gut] 2023 Feb; Vol. 72 (2), pp. 381-391. Date of Electronic Publication: 2022 Jul 04.
DOI:	10.1136/gutjnl-2022-327196
Abstrakt:	Objective: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. Design: Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). Results: Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10 -9 , OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10 -5 , OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10 -44 ). Conclusion: This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis. Competing Interests: Competing interests: JT has received speaking and/or consulting fees from Versantis, Gore, Bayer, Alexion, Norgine, Grifols and CSL Behring. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)
Databáze:	MEDLINE
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