I148M variant in PNPLA3 reduces central adiposity and metabolic disease risks while increasing nonalcoholic fatty liver disease

Background & Aims The I148M variant because of the substitution of C to G in PNPLA3 (rs738409) is associated with the increased risk of nonalcoholic fatty liver disease (NAFLD). In liver, I148M variant reduces hydrolytic function of PNPLA3, which results in hepatic steatosis; however, its association with the other clinical phenotype such as adiposity and metabolic diseases is not well established. Methods To identify the impact of I148M variant on clinical risk factors of NAFLD, we recruited 1363 generally healthy Korean males after excluding alcoholic and secondary causes of hepatic steatosis. Central adiposity was assessed by computed tomography, and hepatic steatosis was evaluated by abdominal ultrasonography. Results The participants were predominantly middle‐aged (49.0 ± 7.1 years; range 30–60 years), and the frequency of NAFLD was 44.2%. The rs738409‐G allele carriers had a 1.19‐fold increased risk for NAFLD (minor allele frequency 0.43; allelic odds ratio 1.38; P = 4.3 × 10−5). Interestingly, the rs738409 GG carriers showed significantly lower levels of visceral and subcutaneous adiposity (P