Stephan Buch
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...
Authors
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 IRVING mrzwi@nottingham.ac.uk
Professor of Virology
JOANNE MORLING JOANNE.MORLING@NOTTINGHAM.AC.UK
Professor of Public Health and Epidemiology
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, 72(2), 381-391. 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 Publishing Group |
Peer Reviewed | Peer Reviewed |
Volume | 72 |
Issue | 2 |
Pages | 381-391 |
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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