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 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 Lucien Irving; Joanne R. Morling; Indra Neil Guha; Eleanor Barnes; M. Azim Ansari; Jocelyn Quistrebert; Luca Valenti; Sascha A. Müller; Marsha Yvonne Morgan; Jean François Dufour; Jonel Trebicka; Thomas Berg; Pierre Deltenre; Sebastian 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 Krawczyk, Markus Casper, Frank Lammert, Florian Eyer, Arndt Vogel, Silke Marhenke, Johann Von Felden, Rohini Sharma, Stephen Rahul Atkinson, Andrew McQuillin, Jacob NattermannClemens 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 Lucien Irving, Joanne R. Morling, Indra Neil Guha, Eleanor Barnes, M. Azim Ansari, Jocelyn Quistrebert, Luca Valenti, Sascha A. Müller, Marsha Yvonne Morgan, Jean François Dufour, Jonel Trebicka, Thomas Berg, Pierre Deltenre, Sebastian Mueller, Jochen Hampe, Felix Stickel

^*Corresponding author for this work

39 Citations (Scopus)

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
Journal	Gut
Volume	72
Issue number	2
Pages (from-to)	381-391
Number of pages	11
ISSN	0017-5749
DOIs	https://doi.org/10.1136/gutjnl-2022-327196
Publication status	Published - 02.2023

Funding

This work was supported by grants from LiSyMKrebs (DEEP-HCC) network funded by the German Federal Ministry for Education and Research (BMBF) to JH (BMBF grant number 031L0258A). JT was supported by the German Research Foundation (DFG) project ID 403224013- SFB 1382 (A09), by the German Federal Ministry of Education and Research (BMBF) for the DEEP-HCC project and by the Hessian Ministry of Higher Education, Research and the Arts (HMWK) for the ENABLE and ACLF-I cluster projects. This work was further supported by grants from the Swiss National Funds (SNF no. 310030_169196) and the Swiss Foundation for Alcohol Research (SSA) to FS. HDN and US were supported by a grant from the Deutsche Krebshilfe (70112169). HI is supported by a viral hepatitis fellowship from the Medical Research Foundation (C0825). JM is funded by the UK Medical Research Council (MC_UU_12014/1) and the Medical Research Foundation (C0365). EB is funded by the Medical Research Council UK, the Oxford NIHR Biomedical Research Centre and is an NIHR Senior Investigator. The STOP-HCV study was funded by a grant from the Medical Research Council, UK (grant MR/K01532X/1). This work was also supported by the Deliver study funded by Cancer Research UK (C30358/A29725). See: https://www.oxcode.ox.ac.uk/research-showcase/liver-cancer . AL is supported by the funds of European Commission through the 'European funds for regional development' (EFRE) as well as by the regional Ministry of Economy, Science and Digitalization of Saxony-Anhalt as part of the 'Autonomy in old Age' (AiA) research group for “LiLife” Project (Project ID: ZS/2018/11/95324). The MICROB-PREDICT (project ID 825694), DECISION (project ID 847949), GALAXY (project ID 668031), LIVERHOPE (project ID 731875), and IHMCSA (project ID 964590) projects have received funding from the European Union’s Horizon 2020 research and innovation programme. This research has been conducted using the UK Biobank resource: application number: 8764. This research was further supported by the BioBank Dresden resource ( https://www.nct-dresden.de/forschung/core-units/biobank-dresden.html ).

Funders	Funder number
Not added

Research Areas and Centers

Centers: University Cancer Center Schleswig-Holstein (UCCSH)
Research Area: Luebeck Integrated Oncology Network (LION)

DFG Research Classification Scheme

2.22-14 Hematology, Oncology
2.11-05 General Genetics and Functional Genome Biology

UN SDGs

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

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10.1136/gutjnl-2022-327196

Cite this

Buch, S., Innes, H., Lutz, P. L., Nischalke, H. D., Marquardt, J. U., Fischer, J., Weiss, K. H., Rosendahl, J., Marot, A., Krawczyk, M., Casper, M., Lammert, F., Eyer, F., Vogel, A., Marhenke, S., Von Felden, J., Sharma, R., Atkinson, S. R., 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{6246487a91c04fbeac4d48924be0367d,

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.",

author = "Stephan Buch and Hamish Innes and Lutz, \{Philipp Ludwig\} and Nischalke, \{Hans Dieter\} and Marquardt, \{Jens U.\} and Janett Fischer and Weiss, \{Karl Heinz\} and Jonas Rosendahl and Astrid Marot and Marcin Krawczyk and Markus Casper and Frank Lammert and Florian Eyer and Arndt Vogel and Silke Marhenke and \{Von Felden\}, Johann and Rohini Sharma and Atkinson, \{Stephen Rahul\} 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 Stauber, \{Rudolf E.\} and Ali Canbay and Alexander Link and Thomas Reiberger and Mattias Mandorfer and Georg Semmler and Bernhard Scheiner and Christian Datz and Stefano Romeo and \{Ginanni Corradini\}, Stefano 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 M{\"u}ller, \{Sascha A.\} and Morgan, \{Marsha Yvonne\} and Dufour, \{Jean Fran{\c c}ois\} and Jonel Trebicka and Thomas Berg and Pierre Deltenre and Sebastian Mueller and Jochen Hampe and Felix Stickel",

note = "Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.",

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, Lutz, PL, Nischalke, HD, Marquardt, JU, Fischer, J, Weiss, KH, Rosendahl, J, Marot, A, Krawczyk, M, Casper, M, Lammert, F, Eyer, F, Vogel, A, Marhenke, S, Von Felden, J, Sharma, R, Atkinson, SR, McQuillin, A, Nattermann, J, Schafmayer, C, Franke, A, Strassburg, C, Rietschel, M, Altmann, H, Sulk, S, Thangapandi, VR, Brosch, M, Lackner, C, Stauber, RE, Canbay, A, Link, A, Reiberger, T, Mandorfer, M, Semmler, G, Scheiner, B, Datz, C, Romeo, S, Ginanni Corradini, S, Irving, WL, Morling, JR, Guha, IN, Barnes, E, Ansari, MA, Quistrebert, J, Valenti, L, Müller, SA, Morgan, MY, Dufour, JF, 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

T2 - 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

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.

UR - https://www.scopus.com/pages/publications/85134687219

U2 - 10.1136/gutjnl-2022-327196

DO - 10.1136/gutjnl-2022-327196

M3 - Journal articles

C2 - 35788059

AN - SCOPUS:85134687219

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

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UN SDGs

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