Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers

Stickel, Felix; Lutz, Philipp; Buch, Stephan; Nischalke, Hans Dieter; Silva, Ines; Rausch, Vanessa; Fischer, Janett; Weiss, Karl Heinz; Gotthardt, Daniel; Rosendahl, Jonas; Marot, Astrid; Elamly, Mona; Krawczyk, Marcin; Casper, Markus; Lammert, Frank; Buckley, Thomas WM; McQuillin, Andrew; Spengler, Ulrich; Eyer, Florian; Vogel, Arndt; Marhenke, Silke; Felden, Johann von; Wege, Henning; Sharma, Rohini; Atkinson, Stephen; Franke, Andre; Nehring, Sophie; Moser, Vincent; Schafmayer, Clemens; Spahr, Laurent; Lackner, Carolin; Stauber, Rudolf E.; Canbay, Ali; Link, Alexander; Valenti, Luca; Grove, Jane I.; Aithal, Guruprasad P.; Marquardt, Jens U.; Fateen, Waleed; Zopf, Steffen; Dufour, Jean-Francois; Trebicka, Jonel; Datz, Christian; Deltenre, Pierre; Mueller, Sebastian; Berg, Thomas; Hampe, Jochen; Morgan, Marsha Y

Abstract

Background & 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 PNPLA3 rs738409:G. This study explores the riskassociations 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 alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for both cirrhosis (OR 0.79 [95% 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), while carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR 1.70 [95% CI 1.54-1.88], p=1.52x10-26) 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 II diabetes mellitus 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 (p=1.72×10−4; ORallelic, 0.75; 95% CI, 0.64–0.87).
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.

Citation

Stickel, F., Lutz, P., Buch, S., Nischalke, H. D., Silva, I., Rausch, V., …Morgan, M. Y. (2020). Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers. Hepatology, 72(1), 88-102. https://doi.org/10.1002/hep.30996

• Journal Article Type: Article
• Acceptance Date: Sep 19, 2019
• Online Publication Date: May 20, 2020
• Publication Date: Jul 14, 2020
• Deposit Date: Oct 17, 2019
• Publicly Available Date: May 21, 2021
• Journal: Hepatology
• Print ISSN: 0270-9139
• Electronic ISSN: 1527-3350
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 72
• Issue: 1
• Pages: 88-102
• DOI: https://doi.org/10.1002/hep.30996
• Keywords: adiponutrin; candidate genes; fibrosis; genetic risk association; genetic susceptibility; host genetics; lipotoxicity.
• Public URL: https://nottingham-repository.worktribe.com/output/2852031
• Publisher URL: https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30996
• Additional Information: This is the peer reviewed version of the following article: Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers, Felix Stickel Philipp Lutz Stephan Buch Hans Dieter Nischalke Ines Silva Vanessa Rausch Janett Fischer Karl Heinz Weiss Daniel Gotthardt Jonas Rosendahl Astrid Marot Mona Elamly Marcin Krawczyk Markus Casper Frank Lammert Thomas WM Buckley Andrew McQuillin Ulrich Spengler Florian Eyer Arndt Vogel Silke Marhenke Johann von Felden Henning Wege Rohini Sharma Stephen Atkinson Andre Franke Sophie Nehring Vincent Moser Clemens Schafmayer Laurent Spahr Carolin Lackner Rudolf E. Stauber Ali Canbay Alexander Link Luca Valenti Jane I. Grove Guruprasad P. Aithal Jens U. Marquardt Waleed Fateen Steffen Zopf Jean‐Francois Dufour Jonel Trebicka Christian Datz Pierre Deltenre Sebastian Mueller Thomas Berg Jochen Hampe Marsha Y Morgan , which has been published in final form at https://doi.org/10.1002/hep.30996. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
• Contract Date: Oct 17, 2019