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 ethnic groups. To identify genetic variants contributing to differences in hepatic fat content, we performed a genome-wide association scan of nonsynonymous sequence variations (n=9,229) in a multiethnic population. An allele in PNPLA3 (rs738409; 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 > 2-fold higher in PNPLA3-148M homozygotes than in noncarriers. Resequencing revealed another allele associated with lower hepatic fat content in African-Americans, the group at lowest risk of NAFLD. Thus, variation in PNPLA3 contributes to ethnic and inter-individual differences in hepatic fat content and susceptibility to NAFLD.

Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 30 September 2008

Publication date (Electronic): 25 September 2008

Publication date (Print): December 2008

Publication date PMC-release: 1 June 2009

Volume: 40

Issue: 12

Pages: 1461-1465

Affiliations

[1 ] Donald W. Reynolds Cardiovascular Clinical Research Center, Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard Dallas, Texas 75390-8591, USA

[2 ] Department of Clinical Sciences, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard Dallas, Texas 75390-8591, USA

[3 ] Department of Statistical Science, Southern Methodist University, Dallas, Texas 75275-0332, USA

[4 ] Perlegen Sciences, Mountain View, California, 94043, USA

[5 ] Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720 and U.S. Department of Energy Joint Genome Institute, Walnut Creek, California 94598, USA

[6 ] Human Genetics Center and Institute for Molecular Medicine, University of Texas Health Science Center, Houston, Texas 77030, USA

[7 ] Howard Hughes Medical Institute at the University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard Dallas, Texas 75390-8591, USA

Author notes

Correspondence should be addressed to H.H.H. ( helen.hobbs@ 123456utsouthwestern.edu ) or J.C.C. ( jonathan.cohen@ 123456utsouthwestern.edu )

[*]

These authors contributed equally to this work.

Article

Manuscript ID: nihpa70399

DOI: 10.1038/ng.257

PMC ID: 2597056

PubMed ID: 18820647

Funding

Funded by: National Heart, Lung, and Blood Institute : NHLBI

Award ID: RL1 HL092550-02 ||HL

Funded by: National Heart, Lung, and Blood Institute : NHLBI

Award ID: P01 HL020948-317281 ||HL

Categories

Subject: Article