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 Marquardt, Janett Fischer, Karl Heinz Weiss, Jonas Rosendahl, Astrid Marot, Marcin Krawcyk, Markus Casper, Frank Lammert, Florian Eyer, Ardnt Vogel, Silke Marhenke, Johann von Felden, Rohini Sharma, Stephen Rhaul Atkinson, Andrew McQuillin, Jacob NattermannClemens Schafmayer, Andre Franke, Christian Strassburg, Marcella Rietschel, Heidi Altmann, Stefan Sulk, Veera Raghavan Thangapandi, Mario Brosch, Carolin Lackner, Rudolf Stauber, Ali Canbay, Alexander Link, Thomas Reiberger, Mattias Mandorfer, Georg Semmler, Benhard Scheiner, Christian Datz, Stefano Romeo, Stefano Ginanni Corradini, William Irving, Joanne Morling, Indra Neil Guha, Eleanor Barnes, M Azim Ansari, Jocelyn Quistrebert, Luca Valenti, Sascha Muller, Marsha Morgan, Jean-Francois Dufour, Jonel Trebicka, Thomas Berg, Pierre Deltenre, Sebasian Mueller, Jochen Hampe, Felix Stickel

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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.
Original languageEnglish
Number of pages11
JournalGut
Early online date4 Jul 2022
DOIs
Publication statusE-pub ahead of print - 4 Jul 2022

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