Meta-Analysis

. 2023 Feb;72(2):381-391.

doi: 10.1136/gutjnl-2022-327196. Epub 2022 Jul 4.

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

Stephan Buch^#^{1

2}, Hamish Innes^#^{3

4}, Philipp Ludwig Lutz⁵, Hans Dieter Nischalke⁵, Jens U Marquardt⁶, Janett Fischer⁷, Karl Heinz Weiss⁸, Jonas Rosendahl⁹, Astrid Marot^{10

11}, Marcin Krawczyk^{12

13}, Markus Casper¹², Frank Lammert¹², Florian Eyer¹⁴, Arndt Vogel¹⁵, Silke Marhenke¹⁵, Johann von Felden¹⁶, Rohini Sharma¹⁷, Stephen Rahul Atkinson¹⁷, Andrew McQuillin¹⁸, Jacob Nattermann⁵, Clemens Schafmayer¹⁹, Andre Franke²⁰, Christian Strassburg⁵, Marcella Rietschel²¹, Heidi Altmann²², Stefan Sulk²², Veera Raghavan Thangapandi^{2

22}, Mario Brosch^{2

22}, Carolin Lackner²³, Rudolf E Stauber²⁴, Ali Canbay²⁵, Alexander Link²⁶, Thomas Reiberger²⁷, Mattias Mandorfer²⁷, Georg Semmler²⁷, Bernhard Scheiner²⁷, Christian Datz²⁸, Stefano Romeo^{29

30}, Stefano Ginanni Corradini³¹, William Lucien Irving³², Joanne R Morling³³, Indra Neil Guha³⁴, Eleanor Barnes³⁵, M Azim Ansari³⁶, Jocelyn Quistrebert³⁶, Luca Valenti³⁷, Sascha A Müller³⁸, Marsha Yvonne Morgan³⁹, Jean-François Dufour⁴⁰, Jonel Trebicka⁴¹, Thomas Berg⁴², Pierre Deltenre^#^{10

11}, Sebastian Mueller^#⁴³, Jochen Hampe^#^{2

22}, Felix Stickel^#^{44

45}

Affiliations

¹ Department of Medicine I, Dresden University Hospital, Dresden, Germany Stephan.buch@uniklinikum-dresden.de.
² Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany.
³ School of Health and Life Sciences, Glasgow Caledonian University School of Health and Life Sciences, Glasgow, UK.
⁴ NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁵ Department of Internal Medicine I, University of Bonn, Bonn, Germany.
⁶ Department of Medicine I, University of Luebeck Human Medicine, Lubeck, Germany.
⁷ Department of Gastroenterology and Rheumatology, Section Hepatology, Leipzig University, Leipzig, Germany.
⁸ Department of Internal Medicine, Krankenhaus Salem, Heidelberg, Germany.
⁹ Department of Gastroenterology, University Hospital Halle, Halle, Germany.
¹⁰ Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
¹¹ Department of Gastroenterology and Hepatology, CHU UCL Namur, Université catholique de Louvain, Louvain-la-Neuve, Belgium.
¹² Department of Medicine II, Saarland University Medical Center, Saarland University, Saarbrucken, Germany.
¹³ Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warszawa, Poland.
¹⁴ Department of Clinical Toxicology, Klinikum Rechts der Isar, Technical University of Munich, Munchen, Germany.
¹⁵ Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
¹⁶ Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁷ Hammersmith Hospital Campus, Imperial College, London, UK.
¹⁸ Molecular Psychiatry Laboratory, University College London, London, UK.
¹⁹ Department of General Surgery, Rostock University Medical Center, Rostock, Germany.
²⁰ Institute for Clinical Molecular Biology, Kiel University, Kiel, Germany.
²¹ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
²² Department of Medicine I, University Hospital Dresden, Dresden, Germany.
²³ Institute of Pathology, University of Graz, Graz, Austria.
²⁴ Department of Internal Medicine, University of Graz, Graz, Austria.
²⁵ Department of Internal Medicine, Ruhr-Universitat Bochum, Bochum, Germany.
²⁶ Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke Universitat Magdeburg, Magdeburg, Germany.
²⁷ Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Wien, Austria.
²⁸ Department of Internal Medicine, General Hospital Oberndorf, Paracelsus Medical University Salzburg, Salzburg, Austria.
²⁹ Department of Molecular and Clinical Medicine, University of Gothenburg, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, Gothenburg, Sweden.
³⁰ Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy.
³¹ Division of Gastroenterology, Department of Translational and Precision Medicine, University of Rome La Sapienza, Rome, Italy.
³² Microbiology, University of Nottingham, Nottingham, UK.
³³ Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.
³⁴ Nottingham Digestive Diseases NIHR Biomedical Research Unit, University Hospital, Nottingham, UK.
³⁵ Nuffield Department of Medicine, University of Oxford, Oxford, UK.
³⁶ Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
³⁷ Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
³⁸ Department of Surgery, Hirslanden Klinik Beau-Site, Bern, Switzerland.
³⁹ Division of Medicine, Royal Free Campus, UCL Institute for Liver and Digestive Health, London, UK.
⁴⁰ Department of BioMedical Research, University of Bern, Bern, Switzerland.
⁴¹ Gastroenterology, Hepatology, Endocrinology and Clinical Infectiology, University of Münster, Münster, Germany.
⁴² Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig University, Leipzig, Germany.
⁴³ Salem Medical Center, Department of Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany.
⁴⁴ Department of Gatroenterology and Hepatology, University of Zürich, Zürich, Switzerland.
⁴⁵ Hirslanden Klinik Beau-Site, Bern, Switzerland.

^# Contributed equally.

PMID: 35788059
PMCID: PMC9872243
DOI: 10.1136/gutjnl-2022-327196

Meta-Analysis

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

Stephan Buch et al. Gut. 2023 Feb.

. 2023 Feb;72(2):381-391.

doi: 10.1136/gutjnl-2022-327196. Epub 2022 Jul 4.

Authors

Affiliations

¹ Department of Medicine I, Dresden University Hospital, Dresden, Germany Stephan.buch@uniklinikum-dresden.de.
² Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany.
³ School of Health and Life Sciences, Glasgow Caledonian University School of Health and Life Sciences, Glasgow, UK.
⁴ NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁵ Department of Internal Medicine I, University of Bonn, Bonn, Germany.
⁶ Department of Medicine I, University of Luebeck Human Medicine, Lubeck, Germany.
⁷ Department of Gastroenterology and Rheumatology, Section Hepatology, Leipzig University, Leipzig, Germany.
⁸ Department of Internal Medicine, Krankenhaus Salem, Heidelberg, Germany.
⁹ Department of Gastroenterology, University Hospital Halle, Halle, Germany.
¹⁰ Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
¹¹ Department of Gastroenterology and Hepatology, CHU UCL Namur, Université catholique de Louvain, Louvain-la-Neuve, Belgium.
¹² Department of Medicine II, Saarland University Medical Center, Saarland University, Saarbrucken, Germany.
¹³ Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warszawa, Poland.
¹⁴ Department of Clinical Toxicology, Klinikum Rechts der Isar, Technical University of Munich, Munchen, Germany.
¹⁵ Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
¹⁶ Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁷ Hammersmith Hospital Campus, Imperial College, London, UK.
¹⁸ Molecular Psychiatry Laboratory, University College London, London, UK.
¹⁹ Department of General Surgery, Rostock University Medical Center, Rostock, Germany.
²⁰ Institute for Clinical Molecular Biology, Kiel University, Kiel, Germany.
²¹ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
²² Department of Medicine I, University Hospital Dresden, Dresden, Germany.
²³ Institute of Pathology, University of Graz, Graz, Austria.
²⁴ Department of Internal Medicine, University of Graz, Graz, Austria.
²⁵ Department of Internal Medicine, Ruhr-Universitat Bochum, Bochum, Germany.
²⁶ Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke Universitat Magdeburg, Magdeburg, Germany.
²⁷ Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Wien, Austria.
²⁸ Department of Internal Medicine, General Hospital Oberndorf, Paracelsus Medical University Salzburg, Salzburg, Austria.
²⁹ Department of Molecular and Clinical Medicine, University of Gothenburg, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, Gothenburg, Sweden.
³⁰ Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy.
³¹ Division of Gastroenterology, Department of Translational and Precision Medicine, University of Rome La Sapienza, Rome, Italy.
³² Microbiology, University of Nottingham, Nottingham, UK.
³³ Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.
³⁴ Nottingham Digestive Diseases NIHR Biomedical Research Unit, University Hospital, Nottingham, UK.
³⁵ Nuffield Department of Medicine, University of Oxford, Oxford, UK.
³⁶ Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
³⁷ Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
³⁸ Department of Surgery, Hirslanden Klinik Beau-Site, Bern, Switzerland.
³⁹ Division of Medicine, Royal Free Campus, UCL Institute for Liver and Digestive Health, London, UK.
⁴⁰ Department of BioMedical Research, University of Bern, Bern, Switzerland.
⁴¹ Gastroenterology, Hepatology, Endocrinology and Clinical Infectiology, University of Münster, Münster, Germany.
⁴² Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig University, Leipzig, Germany.
⁴³ Salem Medical Center, Department of Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany.
⁴⁴ Department of Gatroenterology and Hepatology, University of Zürich, Zürich, Switzerland.
⁴⁵ Hirslanden Klinik Beau-Site, Bern, Switzerland.

^# Contributed equally.

PMID: 35788059
PMCID: PMC9872243
DOI: 10.1136/gutjnl-2022-327196

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.

PubMed Disclaimer

Conflict of interest statement

Competing interests: JT has received speaking and/or consulting fees from Versantis, Gore, Bayer, Alexion, Norgine, Grifols and CSL Behring.

Figures

**Figure 1**
Genome-wide association study (Discovery GWAS) results. Principal findings of genetic analyses. (A): Manhattan plot of genome-wide association results for alcohol-related hepatocellular carcinoma (HCC) in the primary discovery cohort. P values (−log10) are shown for SNPs that passed quality control. The genome-wide significance threshold (5×10⁻⁸) is shown as a black line. The threshold for replication follow-up (p<5×10⁻⁶) is shown as a dashed line. Gene names for replicating loci (table 2) are shown. Variants with significance p<5×10⁻⁸ are highlighted in red, those with p<5×10⁻⁶ are highlighted in green. (B) Locus plot for HCC risk locus *PNPLA3*. The −log10 (p values, meta-analysis of discovery and replication samples) are plotted against SNP genomic position based on NCBI Build 37, with the names and location of nearest genes shown at the bottom. The variant with the lowest p value (lead variant) in the discovery analysis in the region is marked by a purple diamond. SNPs are coloured to reflect correlation with the most significant SNP, with red denoting the highest LD (r2 >0.8) with the lead SNP. The top association signal is located in exon 3 of *PNPLA3*. Estimated recombination rates from the 1000 Genomes Project (hg19, EUR population) are plotted in blue to reflect the local LD structure. (C) Locus plot for HCC risk locus *TM6SF2*. The top association signal is located in exon 6 of *TM6SF2*. (D) Locus plot for HCC risk locus *TERT*. Fine-mapping analysis of the *TERT* association signals. Annotated LD-Blocks are clusters of strong pairwise LD SNPs and reflect the LD pattern in the Discovery GWAS cohort. The lead association signal is located in intron 4 of the *TERT* gene (annotated on the reverse strand), located in LD block B-3 spanning from intron 4 to intron 2 of *TERT*. NCBI, National Center for Biotechnology Information; SNP, single-nucleotide polymorphism.

**Figure 2**
Association between novel (*TERT*) and confirmed loci (*PNPLA3*, *TM6SF2*) with HCC and cirrhosis phenotypes. ORs and 95% CIs for the susceptibility loci for alcohol-related HCC and alcohol-related cirrhosis (ArC) in comparison to alcohol misusers without cirrhosis (AM). The comparison HCC vs ArC displays allelic ORs of combined stage 1 and 2 samples (meta-analysis), derived from allele dosage data, adjusted for age, sex, BMI, type 2 diabetes status and top 15 principal components of genetic ancestry. *The comparison HCC versus AM and ArC versus AM display unadjusted allelic ORs derived from 2×2 contingency tables of allele counts observed in the total cohort, provided in online supplemental tables 2–4. BMI, body mass index; HCC, hepatocellular carcinoma.

See this image and copyright information in PMC

Comment in

enHanCCing knowledge of genetic factors in primary liver tumor.
Koshiol J, Krawczyk M. Koshiol J, et al. Hepatology. 2024 Jul 1;80(1):11-13. doi: 10.1097/HEP.0000000000000771. Epub 2024 Feb 13. Hepatology. 2024. PMID: 38349672 Free PMC article. No abstract available.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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