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 W M; McQuillin, Andrew; Spengler, Ulrich; Eyer, Florian; Vogel, Arndt; Marhenke, Silke; von Felden, Johann; 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     «

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 W M; McQuillin, Andrew; Spengler, Ulrich; Eyer, Florian; Vogel, Arndt; Marhenke, Silke; von Felden, Johann; Wege, Henning; Sharma, Rohini; Atkinson, Stephen; Franke, Andre; Nehring, Sophie; Moser, Vincent; Schafmayer, Clemens; Spahr...     »

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 PNPLA3 rs738409:G. This study explores the risk association...     »