Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis

Felix Stickel; Stephan Buch; Hans Dieter Nischalke; Karl Heinz Weiss; Daniel Gotthardt; Janett Fischer; Jonas Rosendahl; Astrid Marot; Mona Elamly; Markus Casper; Frank Lammert; Andrew McQuillin; Steffen Zopf; Ulrich Spengler; Silke Marhenke; Martha M Kirstein; Arndt Vogel; Florian Eyer; Johann von Felden; Henning Wege; Thorsten Buch; Clemens Schafmayer; Felix Braun; Pierre Deltenre; Thomas Berg; Marsha Y Morgan; Jochen Hampe

doi:10.1038/s41395-018-0041-8

Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis

Am J Gastroenterol. 2018 Oct;113(10):1475-1483. doi: 10.1038/s41395-018-0041-8. Epub 2018 Mar 13.

Authors

Felix Stickel¹, Stephan Buch¹, Hans Dieter Nischalke¹, Karl Heinz Weiss¹, Daniel Gotthardt¹, Janett Fischer¹, Jonas Rosendahl¹, Astrid Marot¹, Mona Elamly¹, Markus Casper¹, Frank Lammert¹, Andrew McQuillin¹, Steffen Zopf¹, Ulrich Spengler¹, Silke Marhenke¹, Martha M Kirstein¹, Arndt Vogel¹, Florian Eyer¹, Johann von Felden¹, Henning Wege¹, Thorsten Buch¹, Clemens Schafmayer¹, Felix Braun¹, Pierre Deltenre¹, Thomas Berg¹, Marsha Y Morgan¹, Jochen Hampe¹

Affiliation

¹ Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland. Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany. Department of Internal Medicine I, University of Bonn, Bonn, Germany. Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany. Hepatology Section, Division of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany. Department of Gastroenterology, University Hospital Halle/Saale, Halle, Germany. Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland. Department of Medicine II, Saarland University Medical Center, Homburg, Germany. Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK. Medical Department 1, University of Erlangen, Nuremberg, Bavaria, Germany. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany. Department of Clinical Toxicology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Institute of Laboratory Animal Science, University of Zurich, Schlieren, Switzerland. Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, United Kingdom. These authors have contributed equally to the presented work and share premier authorship: Felix Stickel, Stephan Buch. These authors have contributed equally to the presented work and share senior authorship: Pierre Deltenre, Thomas Berg, Marsha Y. Morgan, and Jochen Hampe.

PMID: 29535416
DOI: 10.1038/s41395-018-0041-8

Abstract

Objectives: Variants in patatin-like phospholipase domain-containing 3 (PNPLA3; rs738409), transmembrane 6 superfamily member 2 (TM6SF2; rs58542926), and membrane bound O-acyltransferase domain containing 7 (MBOAT7; rs641738) are risk factors for the development of alcohol-related cirrhosis. Within this population, PNPLA3 rs738409 is also an established risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to explore possible risk associations of TM6SF2 rs58542926 and MBOAT7 rs641738 with HCC.

Methods: Risk variants in PNPLA3, TM6SF2, and MBOAT7 were genotyped in 751 cases with alcohol-related cirrhosis and HCC and in 1165 controls with alcohol-related cirrhosis without HCC. Association with the risk of developing HCC was analyzed using multivariate logistic regression.

Results: The development of HCC was independently associated with PNPLA3 rs738409 (OR_adjusted 1.84 [95% CI 1.55-2.18], p = 1.85 × 10^-12) and TM6SF2 rs58542926 (OR_adjusted 1.66 [1.30-2.13], p = 5.13 × 10^-05), using an additive model, and controlling the sex, age, body mass index, and type 2 diabetes mellitus; the risk associated with carriage of MBOAT7 rs641738 (OR_adjusted 1.04 [0.88-1.24], p = 0.61) was not significant. The population-attributable fractions were 43.5% for PNPLA3 rs738409, 11.5% for TM6SF2 rs58542926, and 49.9% for the carriage of both the variants combined.

Conclusions: Carriage of TM6SF2 rs58542926 is an additional risk factor for the development of HCC in people with alcohol-related cirrhosis. Carriage of both PNPLA3 rs738409 and TM6SF2 rs58542926 accounts for half of the attributable risk for HCC in this population. Genotyping will allow for more precise HCC risk-stratification of patients with alcohol-related cirrhosis, and genotype-guided screening algorithms would optimize patient care.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Acyltransferases / genetics*
Aged
Carcinoma, Hepatocellular / genetics*
Carcinoma, Hepatocellular / pathology
Case-Control Studies
Disease Progression
Europe
Female
Genetic Predisposition to Disease
Genotype
Humans
Lipase / genetics*
Liver / pathology
Liver Cirrhosis, Alcoholic / genetics*
Liver Cirrhosis, Alcoholic / pathology
Liver Neoplasms / genetics*
Liver Neoplasms / pathology
Male
Membrane Proteins / genetics*
Middle Aged
Polymorphism, Single Nucleotide

Substances

Membrane Proteins
TM6SF2 protein, human
Acyltransferases
MBOAT7 protein, human
Lipase
adiponutrin, human