Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis

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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,PNPLA3rs738409 is also an established risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to explore possible risk associations ofTM6SF2rs58542926 andMBOAT7rs641738 with HCC.METHODS:Risk variants inPNPLA3, TM6SF2, andMBOAT7were 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 withPNPLA3rs738409 (ORadjusted 1.84 [95% CI 1.55-2.18],p= 1.85 × 10-12) andTM6SF2rs58542926 (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 of MBOAT7 rs641738 (ORadjusted 1.04 [0.88-1.24], p = 0.61) was not significant. The population-attributable fractions were 43.5% for PNPLA3rs738409, 11.5% forTM6SF2rs58542926, and 49.9% for the carriage of both the variants combined.CONCLUSIONS:Carriage ofTM6SF2rs58542926 is an additional risk factor for the development of HCC in people with alcohol-related cirrhosis. Carriage of bothPNPLA3rs738409 andTM6SF2rs58542926 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.

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