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

TY - JOUR

T1 - Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study

AU - Buch, Stephan

AU - Innes, Hamish

AU - Lutz, Philipp Ludwig

AU - Nischalke, Hans Dieter

AU - Marquardt, Jens U

AU - Fischer, Janett

AU - Weiss, Karl Heinz

AU - Rosendahl, Jonas

AU - Marot, Astrid

AU - Krawczyk, Marcin

AU - Casper, Markus

AU - Lammert, Frank

AU - Eyer, Florian

AU - Vogel, Arndt

AU - Marhenke, Silke

AU - von Felden, Johann

AU - Sharma, Rohini

AU - Atkinson, Stephen Rahul

AU - McQuillin, Andrew

AU - Nattermann, Jacob

AU - Schafmayer, Clemens

AU - Franke, Andre

AU - Strassburg, Christian

AU - Rietschel, Marcella

AU - Altmann, Heidi

AU - Sulk, Stefan

AU - Thangapandi, Veera Raghavan

AU - Brosch, Mario

AU - Lackner, Carolin

AU - Stauber, Rudolf E

AU - Canbay, Ali

AU - Link, Alexander

AU - Reiberger, Thomas

AU - Mandorfer, Mattias

AU - Semmler, Georg

AU - Scheiner, Bernhard

AU - Datz, Christian

AU - Romeo, Stefano

AU - Ginanni Corradini, Stefano

AU - Irving, William Lucien

AU - Morling, Joanne R

AU - Guha, Indra Neil

AU - Barnes, Eleanor

AU - Ansari, M Azim

AU - Quistrebert, Jocelyn

AU - Valenti, Luca

AU - Müller, Sascha A

AU - Morgan, Marsha Yvonne

AU - Dufour, Jean-François

AU - Trebicka, Jonel

AU - Berg, Thomas

AU - Deltenre, Pierre

AU - Mueller, Sebastian

AU - Hampe, Jochen

AU - Stickel, Felix

N1 - © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2023/2

Y1 - 2023/2

N2 - 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.

AB - 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.

U2 - 10.1136/gutjnl-2022-327196

DO - 10.1136/gutjnl-2022-327196

M3 - SCORING: Journal article

C2 - 35788059

VL - 72

SP - 381

EP - 391

JO - GUT

JF - GUT

SN - 0017-5749

IS - 2

ER -