title: I148M variant in PNPLA3 reduces central adiposity and metabolic disease risks while increasing nonalcoholic fatty liver disease.
abstract: OBJECTIVE
  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 < 0.001 and = 0.015, respectively), BMI (P < 0.001), triglycerides (P < 0.001) and insulin resistance (P = 0.002) compared to CC carriers. These negative associations between clinical risk factors and rs738409-G dosage were more prominent in non-NAFLD group compared to those in NAFLD group.
  
  
  CONCLUSIONS
  The I148M variant, although increasing the risk of NAFLD, was associated with reduced levels of central adiposity, BMI, serum triglycerides and insulin resistance, suggesting differential roles in fat storage and distribution according to cell types and metabolic status.
authors.affiliation: Informatics Program, Boston Children's Hospital, Boston, MA, USA.|Department of Family Medicine, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Family Medicine, Seoul National University Hospital, Seoul, South Korea.
authors.forename: BeLong
authors.initials: B
authors.lastname: Cho
authors.affiliation: Department of Family Medicine, Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, South Korea.
authors.forename: Hyuktae
authors.initials: H
authors.lastname: Kwon
authors.affiliation: Center for Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
authors.forename: Daria
authors.initials: D
authors.lastname: Prilutsky
authors.affiliation: Department of Family Medicine, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Jae Moon
authors.initials: JM
authors.lastname: Yun
authors.affiliation: Department of Family Medicine, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Ho Chun
authors.initials: HC
authors.lastname: Choi
authors.affiliation: School of Computer Science and Engineering, Soongsil University, Seoul, South Korea.
authors.forename: Kyu-Baek
authors.initials: KB
authors.lastname: Hwang
authors.affiliation: Samsung Genome Institute, Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea.
authors.forename: In-Hee
authors.initials: IH
authors.lastname: Lee
authors.affiliation: Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, South Korea.|Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Kim
authors.affiliation: Informatics Program, Boston Children's Hospital, Boston, MA, USA.|Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
authors.forename: Sek Won
authors.initials: SW
authors.lastname: Kong
mesh_terms: D000328:Adult; D015992:Body Mass Index; D020022:Genetic Predisposition to Disease; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008049:Lipase / Q000235:genetics*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008659:Metabolic Diseases / Q000175:diagnosis / Q000235:genetics; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000175:diagnosis / Q000235:genetics; D056128:Obesity, Abdominal / Q000175:diagnosis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D056910:Republic of Korea; D014280:Triglycerides / Q000097:blood; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D008049:Lipase; D008565:Membrane Proteins; D014280:Triglycerides; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
keywords: I148M variant; insulin resistance; nonalcoholic fatty liver disease; obesity; triglyceride