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

Stephan Buch; Hamish Innes; Philipp Ludwig Lutz; Hans Dieter Nischalke; Jens U Marquardt; Janett Fischer; Karl Heinz Weiss; Jonas Rosendahl; Astrid Marot; Marcin Krawczyk; Markus Casper; Frank Lammert; Florian Eyer; Arndt Vogel; Silke Marhenke; Johann von Felden; Rohini Sharma; Stephen Rahul Atkinson; Andrew McQuillin; Jacob Nattermann; Clemens Schafmayer; Andre Franke; Christian Strassburg; Marcella Rietschel; Heidi Altmann; Stefan Sulk; Veera Raghavan Thangapandi; Mario Brosch; Carolin Lackner; Rudolf E Stauber; Ali Canbay; Alexander Link; Thomas Reiberger; Mattias Mandorfer; Georg Semmler; Bernhard Scheiner; Christian Datz; Stefano Romeo; Stefano Ginanni Corradini; William Lucien Irving; Joanne R Morling; Indra Neil Guha; Eleanor Barnes; M Azim Ansari; Jocelyn Quistrebert; Luca Valenti; Sascha A Müller; Marsha Yvonne Morgan; Jean-François Dufour; Jonel Trebicka; Thomas Berg; Pierre Deltenre; Sebastian Mueller; Jochen Hampe; Felix Stickel

doi:10.1136/gutjnl-2022-327196

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

Gut. 2023 Feb;72(2):381-391. doi: 10.1136/gutjnl-2022-327196. Epub 2022 Jul 4.

Authors

Stephan Buch^#^{1

2}, Hamish Innes^#^{3

4}, Philipp Ludwig Lutz⁵, Hans Dieter Nischalke⁵, Jens U Marquardt⁶, Janett Fischer⁷, Karl Heinz Weiss⁸, Jonas Rosendahl⁹, Astrid Marot^{10

11}, Marcin Krawczyk^{12

13}, Markus Casper¹², Frank Lammert¹², Florian Eyer¹⁴, Arndt Vogel¹⁵, Silke Marhenke¹⁵, Johann von Felden¹⁶, Rohini Sharma¹⁷, Stephen Rahul Atkinson¹⁷, Andrew McQuillin¹⁸, Jacob Nattermann⁵, Clemens Schafmayer¹⁹, Andre Franke²⁰, Christian Strassburg⁵, Marcella Rietschel²¹, Heidi Altmann²², Stefan Sulk²², Veera Raghavan Thangapandi^{2

22}, Mario Brosch^{2

22}, Carolin Lackner²³, Rudolf E Stauber²⁴, Ali Canbay²⁵, Alexander Link²⁶, Thomas Reiberger²⁷, Mattias Mandorfer²⁷, Georg Semmler²⁷, Bernhard Scheiner²⁷, Christian Datz²⁸, Stefano Romeo^{29

30}, Stefano Ginanni Corradini³¹, William Lucien Irving³², Joanne R Morling³³, Indra Neil Guha³⁴, Eleanor Barnes³⁵, M Azim Ansari³⁶, Jocelyn Quistrebert³⁶, Luca Valenti³⁷, Sascha A Müller³⁸, Marsha Yvonne Morgan³⁹, Jean-François Dufour⁴⁰, Jonel Trebicka⁴¹, Thomas Berg⁴², Pierre Deltenre^#^{10

11}, Sebastian Mueller^#⁴³, Jochen Hampe^#^{2

22}, Felix Stickel^#^{44

45}

Affiliations

¹ Department of Medicine I, Dresden University Hospital, Dresden, Germany [email protected].
² Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany.
³ School of Health and Life Sciences, Glasgow Caledonian University School of Health and Life Sciences, Glasgow, UK.
⁴ NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁵ Department of Internal Medicine I, University of Bonn, Bonn, Germany.
⁶ Department of Medicine I, University of Luebeck Human Medicine, Lubeck, Germany.
⁷ Department of Gastroenterology and Rheumatology, Section Hepatology, Leipzig University, Leipzig, Germany.
⁸ Department of Internal Medicine, Krankenhaus Salem, Heidelberg, Germany.
⁹ Department of Gastroenterology, University Hospital Halle, Halle, Germany.
¹⁰ Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
¹¹ Department of Gastroenterology and Hepatology, CHU UCL Namur, Université catholique de Louvain, Louvain-la-Neuve, Belgium.
¹² Department of Medicine II, Saarland University Medical Center, Saarland University, Saarbrucken, Germany.
¹³ Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warszawa, Poland.
¹⁴ Department of Clinical Toxicology, Klinikum Rechts der Isar, Technical University of Munich, Munchen, Germany.
¹⁵ Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
¹⁶ Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁷ Hammersmith Hospital Campus, Imperial College, London, UK.
¹⁸ Molecular Psychiatry Laboratory, University College London, London, UK.
¹⁹ Department of General Surgery, Rostock University Medical Center, Rostock, Germany.
²⁰ Institute for Clinical Molecular Biology, Kiel University, Kiel, Germany.
²¹ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
²² Department of Medicine I, University Hospital Dresden, Dresden, Germany.
²³ Institute of Pathology, University of Graz, Graz, Austria.
²⁴ Department of Internal Medicine, University of Graz, Graz, Austria.
²⁵ Department of Internal Medicine, Ruhr-Universitat Bochum, Bochum, Germany.
²⁶ Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke Universitat Magdeburg, Magdeburg, Germany.
²⁷ Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Wien, Austria.
²⁸ Department of Internal Medicine, General Hospital Oberndorf, Paracelsus Medical University Salzburg, Salzburg, Austria.
²⁹ Department of Molecular and Clinical Medicine, University of Gothenburg, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, Gothenburg, Sweden.
³⁰ Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy.
³¹ Division of Gastroenterology, Department of Translational and Precision Medicine, University of Rome La Sapienza, Rome, Italy.
³² Microbiology, University of Nottingham, Nottingham, UK.
³³ Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.
³⁴ Nottingham Digestive Diseases NIHR Biomedical Research Unit, University Hospital, Nottingham, UK.
³⁵ Nuffield Department of Medicine, University of Oxford, Oxford, UK.
³⁶ Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
³⁷ Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
³⁸ Department of Surgery, Hirslanden Klinik Beau-Site, Bern, Switzerland.
³⁹ Division of Medicine, Royal Free Campus, UCL Institute for Liver and Digestive Health, London, UK.
⁴⁰ Department of BioMedical Research, University of Bern, Bern, Switzerland.
⁴¹ Gastroenterology, Hepatology, Endocrinology and Clinical Infectiology, University of Münster, Münster, Germany.
⁴² Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig University, Leipzig, Germany.
⁴³ Salem Medical Center, Department of Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany.
⁴⁴ Department of Gatroenterology and Hepatology, University of Zürich, Zürich, Switzerland.
⁴⁵ Hirslanden Klinik Beau-Site, Bern, Switzerland.

^# Contributed equally.

Abstract

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.

Keywords: genetic polymorphisms; hepatocellular carcinoma.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Hepatocellular* / etiology
Carcinoma, Hepatocellular* / genetics
Case-Control Studies
Diabetes Mellitus, Type 2 / complications
Genetic Predisposition to Disease*
Genetic Variation
Genome-Wide Association Study
Humans
Liver Cirrhosis, Alcoholic* / complications
Liver Cirrhosis, Alcoholic* / genetics
Liver Neoplasms* / etiology
Liver Neoplasms* / genetics
Polymorphism, Single Nucleotide
Risk Factors
Telomerase* / genetics

Substances

Telomerase
TERT protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding