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. 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.
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 (ORadjusted 1.84 [95% CI 1.55-2.18], p = 1.85 × 10-12) and TM6SF2 rs58542926 (ORadjusted 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 (ORadjusted 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.
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, PNPLA3rs738409 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 TM6SF2rs58542926 and MBOAT7rs641738 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 PNPLA3rs738409 (ORadjusted 1.84 [95% CI 1.55-2.18], p = 1.85 × 10-12) and TM6SF2rs58542926 (ORadjusted 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 MBOAT7rs641738 (ORadjusted 1.04 [0.88-1.24], p = 0.61) was not significant. The population-attributable fractions were 43.5% for PNPLA3rs738409, 11.5% for TM6SF2rs58542926, and 49.9% for the carriage of both the variants combined. CONCLUSIONS: Carriage of TM6SF2rs58542926 is an additional risk factor for the development of HCC in people with alcohol-related cirrhosis. Carriage of both PNPLA3rs738409 and TM6SF2rs58542926 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.
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