title: Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.
abstract: Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem of unknown etiology that varies in prevalence among ancestry groups. To identify genetic variants contributing to differences in hepatic fat content, we carried out a genome-wide association scan of nonsynonymous sequence variations (n = 9,229) in a population comprising Hispanic, African American and European American individuals. An allele in PNPLA3 (rs738409[G], encoding I148M) was strongly associated with increased hepatic fat levels (P = 5.9 x 10(-10)) and with hepatic inflammation (P = 3.7 x 10(-4)). The allele was most common in Hispanics, the group most susceptible to NAFLD; hepatic fat content was more than twofold higher in PNPLA3 rs738409[G] homozygotes than in noncarriers. Resequencing revealed another allele of PNPLA3 (rs6006460[T], encoding S453I) that was associated with lower hepatic fat content in African Americans, the group at lowest risk of NAFLD. Thus, variation in PNPLA3 contributes to ancestry-related and inter-individual differences in hepatic fat content and susceptibility to NAFLD.
authors.affiliation: Donald W Reynolds Cardiovascular Clinical Research Center, Eugene McDermott Center for Human Growth and Development, Dallas, TX 75390, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Romeo
authors.forename: Julia
authors.initials: J
authors.lastname: Kozlitina
authors.forename: Chao
authors.initials: C
authors.lastname: Xing
authors.forename: Alexander
authors.initials: A
authors.lastname: Pertsemlidis
authors.forename: David
authors.initials: D
authors.lastname: Cox
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cohen
authors.forename: Helen H
authors.initials: HH
authors.lastname: Hobbs
mesh_terms: D005234:Fatty Liver / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent