Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease

Stefano Romeo, Julia Kozlitina, Chao Xing, Alexander Pertsemlidis, David Cox, Len A. Pennacchio, Eric Boerwinkle, Jonathan C. Cohen, Helen H. Hobbs

Research output: Contribution to journalArticle

1610 Scopus citations

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 × 10 -10) and with hepatic inflammation (P = 3.7 × 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.

Original languageEnglish (US)
Pages (from-to)1461-1465
Number of pages5
JournalNature genetics
Volume40
Issue number12
DOIs
StatePublished - Dec 1 2008

ASJC Scopus subject areas

  • Genetics

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