TY - JOUR
T1 - Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers
AU - Stickel, Felix
AU - Lutz, Philipp
AU - Buch, Stephan
AU - Nischalke, Hans Dieter
AU - Silva, Ines
AU - Rausch, Vanessa
AU - Fischer, Janett
AU - Weiss, Karl Heinz
AU - Gotthardt, Daniel
AU - Rosendahl, Jonas
AU - Marot, Astrid
AU - Elamly, Mona
AU - Krawczyk, Marcin
AU - Casper, Markus
AU - Lammert, Frank
AU - Buckley, Thomas W.M.
AU - McQuillin, Andrew
AU - Spengler, Ulrich
AU - Eyer, Florian
AU - Vogel, Arndt
AU - Marhenke, Silke
AU - von Felden, Johann
AU - Wege, Henning
AU - Sharma, Rohini
AU - Atkinson, Stephen
AU - Franke, Andre
AU - Nehring, Sophie
AU - Moser, Vincent
AU - Schafmayer, Clemens
AU - Spahr, Laurent
AU - Lackner, Carolin
AU - Stauber, Rudolf E.
AU - Canbay, Ali
AU - Link, Alexander
AU - Valenti, Luca
AU - Grove, Jane I.
AU - Aithal, Guruprasad P.
AU - Marquardt, Jens U.
AU - Fateen, Waleed
AU - Zopf, Steffen
AU - Dufour, Jean Francois
AU - Trebicka, Jonel
AU - Datz, Christian
AU - Deltenre, Pierre
AU - Mueller, Sebastian
AU - Berg, Thomas
AU - Hampe, Jochen
AU - Morgan, Marsha Y.
N1 - Funding Information:
The authors thank the Clinical Research Support Service of the CHUV-UNIL, Lausanne, Switzerland, for providing the infrastructure for patient recruitment and collecting phenotypic data.
Publisher Copyright:
© 2019 by the American Association for the Study of Liver Diseases.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85077304939&partnerID=8YFLogxK
U2 - 10.1002/hep.30996
DO - 10.1002/hep.30996
M3 - Journal articles
C2 - 31630428
AN - SCOPUS:85077304939
SN - 0270-9139
VL - 72
SP - 88
EP - 102
JO - Hepatology
JF - Hepatology
IS - 1
ER -
