Felix Stickel1, Philipp Lutz2, Stephan Buch3, Hans Dieter Nischalke2, Ines Silva4, Vanessa Rausch4, Janett Fischer5, Karl Heinz Weiss6, Daniel Gotthardt6, Jonas Rosendahl7, Astrid Marot8, Mona Elamly8, Marcin Krawczyk9,10, Markus Casper9, Frank Lammert9, Thomas W M Buckley11, Andrew McQuillin11, Ulrich Spengler2, Florian Eyer12, Arndt Vogel13, Silke Marhenke13, Johann von Felden14, Henning Wege14, Rohini Sharma15, Stephen Atkinson15, Andre Franke16, Sophie Nehring3, Vincent Moser3, Clemens Schafmayer17, Laurent Spahr18, Carolin Lackner19, Rudolf E Stauber20, Ali Canbay21, Alexander Link21, Luca Valenti22,23, Jane I Grove24,25, Guruprasad P Aithal24,25, Jens U Marquardt26, Waleed Fateen24,25, Steffen Zopf27, Jean-Francois Dufour28, Jonel Trebicka29, Christian Datz30, Pierre Deltenre8, Sebastian Mueller4, Thomas Berg5, Jochen Hampe3, Marsha Y Morgan31. 1. Department of Gastroenterology and Hepatology, University Hospital of Zürich, Switzerland. 2. Department of Internal Medicine I, University of Bonn, Bonn, Germany. 3. Medical Department 1, University Hospital Dresden, TU Dresden, Germany. 4. Department of Internal Medicine and Center for Alcohol Research, Salem Medical Center University Hospital Heidelberg, Heidelberg, Germany. 5. Division of Hepatology, Clinic and Polyclinic for Gastroenterology, Hepatology, Infectiology and Pneumology, University Clinic Leipzig, Leipzig, Germany. 6. Department of Internal Medicine IV, Medical University of Heidelberg, Germany. 7. Department of Gastroenterology, University Hospital Halle/Saale, Germany. 8. Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland. 9. Department of Medicine II, Saarland University Medical Center, Homburg, Germany. 10. Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland. 11. Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, UK. 12. Department of Clinical Toxicology, Klinikum Rechts der Isar, Technical University of Munich, Germany. 13. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany. 14. First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 15. Department of Metabolism, Digestion & Reproduction, Division of Surgery and Cancer, Imperial College London, London, UK. 16. Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany. 17. Department of Visceral and Thoracic Surgery, Kiel University, Kiel, Germany. 18. Departments of Gastroenterology and Hepatology, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland. 19. Institute of Pathology, Medical University of Graz, Austria. 20. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria. 21. Ruhr-Universität Bochum, Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Bochum, Germany. 22. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy. 23. Translational Medicine - Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Milan, Italy. 24. NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK. 25. Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK. 26. Department of Medicine I, Johannes Gutenberg-Universität Mainz, Mainz, Germany. 27. Medical Department 1, University of Erlangen-Nuremberg, Germany. 28. University Clinic for Visceral Surgery and Medicine, Inselspital, University of Berne, Berne, Switzerland. 29. Department of Internal Medicine I, Goethe University Frankfurt, Frankfurt, Germany. 30. Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private Medical University of Salzburg, Oberndorf, Austria. 31. UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, UK.
Abstract
BACKGROUND AND AIMS: Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. APPROACH AND RESULTS: Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,031 with alcohol-related cirrhosis and HCC, 1,653 with alcohol-related cirrhosis without HCC, 2,588 alcohol misusers with no liver disease, and 899 healthy controls. Genetic associations with the risks for developing alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for developing both cirrhosis (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.88; P = 8.13 × 10-6 ) and HCC (OR, 0.77; 95% CI, 0.68-0.89; P = 2.27 × 10-4 ), whereas carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR, 1.70; 95% CI, 1.54-1.88; P = 1.52 × 10-26 ) and HCC (OR, 1.77; 95% CI, 1.58-1.98; P = 2.31 × 10-23 ). These associations remained significant after adjusting for age, sex, body mass index, type 2 diabetes, and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women, but the protective effect against the subsequent development of HCC was only observed in men (ORallelic , 0.75; 95% CI, 0.64-0.87; P = 1.72 × 10-4 ). CONCLUSIONS: Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population.
BACKGROUND AND AIMS: Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. APPROACH AND RESULTS: Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,031 with alcohol-related cirrhosis and HCC, 1,653 with alcohol-related cirrhosis without HCC, 2,588 alcohol misusers with no liver disease, and 899 healthy controls. Genetic associations with the risks for developing alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13rs72613567:TA was associated with a lower risk for developing both cirrhosis (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.88; P = 8.13 × 10-6 ) and HCC (OR, 0.77; 95% CI, 0.68-0.89; P = 2.27 × 10-4 ), whereas carriage of PNPLA3rs738409:G was associated with an increased risk for developing cirrhosis (OR, 1.70; 95% CI, 1.54-1.88; P = 1.52 × 10-26 ) and HCC (OR, 1.77; 95% CI, 1.58-1.98; P = 2.31 × 10-23 ). These associations remained significant after adjusting for age, sex, body mass index, type 2 diabetes, and country. Carriage of HSD17B13rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3rs738409:G in both men and women, but the protective effect against the subsequent development of HCC was only observed in men (ORallelic , 0.75; 95% CI, 0.64-0.87; P = 1.72 × 10-4 ). CONCLUSIONS: Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population.
Authors: Simona Riccio; Rosa Melone; Caterina Vitulano; Pierfrancesco Guida; Ivan Maddaluno; Stefano Guarino; Pierluigi Marzuillo; Emanuele Miraglia Del Giudice; Anna Di Sessa Journal: World J Clin Pediatr Date: 2022-03-23
Authors: Yanling Ma; Suman Karki; Philip M Brown; Dennis D Lin; Maren C Podszun; Wenchang Zhou; Olga V Belyaeva; Natalia Y Kedishvili; Yaron Rotman Journal: J Lipid Res Date: 2020-09-24 Impact factor: 5.922
Authors: Wen-Yue Liu; Mohammed Eslam; Kenneth I Zheng; Hong-Lei Ma; Rafael S Rios; Min-Zhi Lv; Gang Li; Liang-Jie Tang; Pei-Wu Zhu; Xiao-Dong Wang; Christopher D Byrne; Giovanni Targher; Jacob George; Ming-Hua Zheng Journal: J Clin Transl Hepatol Date: 2021-02-22
Authors: Pierre Deltenre; Jochen Hampe; Felix Stickel; Stephan Buch; Hamish Innes; Hans Dieter Nischalke; Indra Neil Guha; Karl Heinz Weiss; Will Irving; Daniel Gotthardt; Eleanor Barnes; Janett Fischer; M Azim Ansari; Jonas Rosendahl; Shang-Kuan Lin; Astrid Marot; Vincent Pedergnana; Markus Casper; Jennifer Benselin; Frank Lammert; John McLauchlan; Philip L Lutz; Victoria Hamill; Sebastian Mueller; Joanne R Morling; Georg Semmler; Florian Eyer; Johann von Felden; Alexander Link; Arndt Vogel; Jens U Marquardt; Stefan Sulk; Jonel Trebicka; Luca Valenti; Christian Datz; Thomas Reiberger; Clemens Schafmayer; Thomas Berg Journal: Hepatol Commun Date: 2021-12-27
Authors: Yanling Ma; Philip M Brown; Dennis D Lin; Jing Ma; Dechun Feng; Olga V Belyaeva; Maren C Podszun; Jason Roszik; Joselyn N Allen; Regina Umarova; David E Kleiner; Natalia Y Kedishvili; Oksana Gavrilova; Bin Gao; Yaron Rotman Journal: Hepatology Date: 2021-03-16 Impact factor: 17.298