Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis. (October 2018)

• Record Type: Journal Article
• Authors: Stickel, Felix; Buch, Stephan; Nischalke, Hans; Weiss, Karl; Gotthardt, Daniel; Fischer, Janett; Rosendahl, Jonas; Marot, Astrid; Elamly, Mona; Casper, Markus; Lammert, Frank; McQuillin, Andrew; Zopf, Steffen; Spengler, Ulrich; Marhenke, Silke; Kirstein, Martha M.; Vogel, Arndt; Eyer, Florian; Felden, Johann; Wege, Henning; Buch, Thorsten; Schafmayer, Clemens; Braun, Felix; Deltenre, Pierre; Berg, Thomas; Morgan, Marsha; Hampe, Jochen
• Is Part Of: American journal of gastroenterology. Volume 113:Number 10(2018)
• Page Start: 1475
• Page End: 1483
• Publication Date: 2018-10
• Subjects: Stomach -- Diseases -- Periodicals; Intestines -- Diseases -- Periodicals; Gastroenterology -- Periodicals; Gastrointestinal Diseases -- Periodicals; Electronic journals; Periodicals; 616.33
• DOI: 10.1038/s41395-018-0041-8
• Languages: English
• ISSNs: 0002-9270

Abstract

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 ofTM6SF2 rs58542926 andMBOAT7 rs641738 with HCC. Methods Risk variants inPNPLA3, TM6SF2, andMBOAT7 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 withPNPLA3 rs738409 (ORadjusted 1.84 [95% CI 1.55-2.18], p = 1.85 × 10-12 ) andTM6SF2 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 ofMBOAT7 rs641738 (ORadjusted 1.04 [0.88-1.24], p = 0.61) was not significant. The population-attributable fractions were 43.5% forPNPLA3 rs738409, 11.5% forTM6SF2 rs58542926, and 49.9% for the carriage of both the variants combined. Conclusions Carriage ofTM6SF2 rs58542926 is an additional risk factor for the development of HCC in people with alcohol-related cirrhosis. Carriage of bothPNPLA3 rs738409 andTM6SF2 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.