Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers

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 (OR allelic , 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.