Human Microbiome Action
Published February 1, 2023 | Version v1
Journal article Open

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

Creators

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

Description

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.

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Additional details

Identifiers

PMID
35788059

Funding

Federal Ministry of Education and Research
LiSyMKrebs (DEEP-HCC) to Jens Marquardt 031L0258A
Federal Ministry of Education and Research
DEP-HCC .
Hessian Ministry for Science and the Arts
ENABLE and ACLF-I cluster projects .
Swiss National Science Foundation
Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study no. 310030_169196
Foundation for Alcohol Research
Felix Stickel .
Medical Research Foundation
Hamish Innes C0825
Research Councils UK
Jens Marquardt MC_UU_12014/1
Medical Research Foundation
Jens Marquardt C0365
Research Councils UK
Eleanor Barnes .
Oxford Biomedical Research
Eleanor Barnes .
Medical Research Council
STOP-HCV study MR/K01532X/1
Cancer Research UK
Deliver Study C30358/ A29725
European Commission
European funds for regional development’ (EFRE) to Alexander Link .
Ministry of Economy, Science and Digitalisation
’Autonomy in old Age’ (AiA) research group for “LiLife” Project ZS/2018/11/95324
European Union
MICROB-PREDICT 825694
European Union
DECISION 847949
European Union
GALAXY 668031
European Union
LIVERHOPE 731875
European Union
IHMCSA 964590

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