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

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

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


Authors

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

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NEIL GUHA neil.guha@nottingham.ac.uk
Professor of Hepatology

Eleanor Barnes

M. Azim Ansari

Jocelyn Quistrebert

Luca Valenti

Sacha A Müller

Marsha Yvonne Morgan

Jean François Dufour

Jonel Trebicka

Thomas Berg

Pierre Deltenre

Sebastian Mueller

Jochen Hampe

Felix Stickel



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.

Citation

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

Journal Article Type Article
Acceptance Date Jun 23, 2022
Online Publication Date Jul 4, 2022
Publication Date Jul 4, 2022
Deposit Date Jul 6, 2022
Publicly Available Date Jul 6, 2022
Journal Gut
Print ISSN 0017-5749
Electronic ISSN 1468-3288
Publisher BMJ
Peer Reviewed Peer Reviewed
DOI https://doi.org/10.1136/gutjnl-2022-327196
Keywords Gastroenterology
Public URL https://nottingham-repository.worktribe.com/output/8852699
Publisher URL https://gut.bmj.com/content/early/2022/07/04/gutjnl-2022-327196

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