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 U. 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 Nattermann; Clemens 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 Lucien Irving; Joanne R. Morling; Indra Neil Guha; Eleanor Barnes; M. Azim  Ansari; Jocelyn  Quistrebert; Luca Valenti; Sascha A. Muller; Marsha Yvonne Morgan; Jean-Francois Dufour; Jonel Trebicka; Thomas Berg; Pierre  Deltenre; Sebasian Mueller; Jochen Hampe; Felix Stickel

doi:10.1136/gutjnl-2022-327196

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 U. 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 Lucien Irving, Joanne R. Morling, Indra Neil Guha, Eleanor Barnes, M. Azim Ansari, Jocelyn Quistrebert, Luca Valenti, Sascha A. Muller, Marsha Yvonne 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 language	English
Pages (from-to)	381-391
Number of pages	11
Journal	Gut
Volume	72
Issue number	2
Early online date	4 Jul 2022
DOIs	https://doi.org/10.1136/gutjnl-2022-327196
Publication status	Published - Feb 2023

Keywords

genetic polymorphisms
hepatocellular carcinoma

ASJC Scopus subject areas

Gastroenterology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1136/gutjnl-2022-327196

Buch, S. et al (2022) Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
Final published version, 1.47 MBLicence: CC BY

Cite this

Buch, S., Innes, H., Ludwig Lutz, P., Dieter Nischalke, H., Marquardt, J. U., Fischer, J., Heinz Weiss, K., Rosendahl, J., Marot, A., Krawcyk, M., Casper, M., Lammert, F., Eyer, F., Vogel, A., Marhenke, S., von Felden, J., Sharma, R., Rhaul Atkinson, S., McQuillin, A., ... 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

@article{2cc39ac76b2f4ab683ea0d36450dd0d5,

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

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.",

keywords = "genetic polymorphisms, hepatocellular carcinoma",

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

year = "2023",

month = feb,

doi = "10.1136/gutjnl-2022-327196",

language = "English",

volume = "72",

pages = "381--391",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

number = "2",

}

Buch, S, Innes, H, Ludwig Lutz, P, Dieter Nischalke, H, Marquardt, JU, Fischer, J, Heinz Weiss, K, Rosendahl, J, Marot, A, Krawcyk, M, Casper, M, Lammert, F, Eyer, F, Vogel, A, Marhenke, S, von Felden, J, Sharma, R, Rhaul Atkinson, S, McQuillin, A, Nattermann, J, Schafmayer, C, Franke, A, Strassburg, C, Rietschel, M, Altmann, H, Sulk, S, Thangapandi, VR, Brosch, M, Lackner, C, Stauber, R, Canbay, A, Link, A, Reiberger, T, Mandorfer, M, Semmler, G, Scheiner, B, Datz, C, Romeo, S, Corradini, SG, Irving, WL, Morling, JR, Guha, IN, Barnes, E, Ansari, MA, Quistrebert, J, Valenti, L, Muller, SA, Morgan, MY, Dufour, J-F, Trebicka, J, Berg, T, Deltenre, P, Mueller, S, Hampe, 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, vol. 72, no. 2, pp. 381-391. https://doi.org/10.1136/gutjnl-2022-327196

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 - Ludwig Lutz, Philipp

AU - Dieter Nischalke, Hans

AU - Marquardt, Jens U.

AU - Fischer, Janett

AU - Heinz Weiss, Karl

AU - Rosendahl, Jonas

AU - Marot, Astrid

AU - Krawcyk, Marcin

AU - Casper, Markus

AU - Lammert, Frank

AU - Eyer, Florian

AU - Vogel, Ardnt

AU - Marhenke, Silke

AU - von Felden, Johann

AU - Sharma, Rohini

AU - Rhaul Atkinson, Stephen

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

AU - Canbay, Ali

AU - Link, Alexander

AU - Reiberger, Thomas

AU - Mandorfer, Mattias

AU - Semmler, Georg

AU - Scheiner, Benhard

AU - Datz, Christian

AU - Romeo, Stefano

AU - Corradini, Stefano Ginanni

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 - Muller, Sascha A.

AU - Morgan, Marsha Yvonne

AU - Dufour, Jean-Francois

AU - Trebicka, Jonel

AU - Berg, Thomas

AU - Deltenre, Pierre

AU - Mueller, Sebasian

AU - Hampe, Jochen

AU - Stickel, Felix

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.

KW - genetic polymorphisms

KW - hepatocellular carcinoma

U2 - 10.1136/gutjnl-2022-327196

DO - 10.1136/gutjnl-2022-327196

M3 - Article

C2 - 35788059

SN - 0017-5749

VL - 72

SP - 381

EP - 391

JO - Gut

JF - Gut

IS - 2

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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