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

Buch S, Innes H, Lutz PL, Nischalke HD, Marquardt JU, Fischer J, Weiss KH, Rosendahl J, Marot A, Krawczyk M, Casper M, Lammert F, Eyer F, Vogel A, Marhenke S, Von Felden J, Sharma R, Atkinson SR, McQuillin A, Nattermann J, Schafmayer C, Franke A, Strassburg C, Rietschel M, Altmann H, Sulk S, Thangapandi VR, Brosch M, Lackner C, Stauber RE, Canbay A, Link A, Reiberger T, Mandorfer M, Semmler G, Scheiner B, Datz C, Romeo S, Ginanni Corradini S, Irving WL, Morling JR, Guha IN, Barnes E, Ansari MA, Quistrebert J, Valenti L, Müller SA, Morgan MY, Dufour JF, Trebicka J, Berg T, Deltenre P, Mueller S, Hampe J, Stickel F (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Book Volume: 72

Pages Range: 381-391

Journal Issue: 2

DOI: 10.1136/gutjnl-2022-327196

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.

Authors with CRIS profile

Involved external institutions

Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Glasgow Caledonian University (GCU) United Kingdom (GB) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Universität zu Lübeck Germany (DE) Universität Leipzig Germany (DE) Krankenhaus Salem Heidelberg Germany (DE) Universitätsklinikum Halle (Saale) Germany (DE) Lausanne University Hospital / Centre hospitalier universitaire vaudois (CHUV) Switzerland (CH) Universität des Saarlandes (UdS) Germany (DE) Technische Universität Dresden Germany (DE) Hirslanden AG / Privatklinikgruppe Hirslanden Switzerland (CH) University College London (UCL) United Kingdom (GB) Klinikum rechts der Isar Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Hammersmith Hospital United Kingdom (GB) Universitätsmedizin Rostock Germany (DE) Christian-Albrechts-Universität zu Kiel Germany (DE) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) Germany (DE) Karl-Franzens-Universität Graz Austria (AT) Ruhr-Universität Bochum (RUB) Germany (DE) Otto-von-Guericke-Universität Magdeburg Germany (DE) Medizinische Universität Wien Austria (AT) Paracelsus Medizinische Privatuniversität Austria (AT) University of Gothenburg / Göteborgs universitet Sweden (SE) University of Nottingham United Kingdom (GB) Nottingham Biomedical Research Centre United Kingdom (GB) University of Oxford United Kingdom (GB) Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico Italy (IT) Universität Bern Switzerland (CH) Westfälische Wilhelms-Universität (WWU) Münster Germany (DE) Universitätsklinikum Leipzig Germany (DE) Ruprecht-Karls-Universität Heidelberg Germany (DE) University of Zurich / Universität Zürich (UZH) Switzerland (CH)

How to cite

APA:

Buch, S., Innes, H., Lutz, P.L., Nischalke, H.D., Marquardt, J.U., Fischer, J.,... Stickel, F. (2023). Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: Results from a genome-wide case-control study. Gut, 72(2), 381-391. https://doi.org/10.1136/gutjnl-2022-327196

MLA:

Buch, Stephan, et al. "Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: Results from a genome-wide case-control study." Gut 72.2 (2023): 381-391.

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