Letter abstract
Nature Genetics 40, 1461 - 1465 (2008)
Published online: 25 September 2008 | doi:10.1038/ng.257
Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease
Stefano Romeo1,8, Julia Kozlitina2,3,8, Chao Xing1,2, Alexander Pertsemlidis1, David Cox4, Len A Pennacchio5, Eric Boerwinkle6, Jonathan C Cohen1 & Helen H Hobbs1,7
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.
- Donald W. Reynolds Cardiovascular Clinical Research Center, Eugene McDermott Center for Human Growth and Development, 6000 Harry Hines Boulevard Dallas, Texas 75390, USA.
- Department of Clinical Sciences, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard Dallas, Texas 75390, USA.
- Department of Statistical Science, Southern Methodist University, Dallas, Texas 75275, USA.
- Perlegen Sciences, Mountain View, California 94043, USA.
- Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720 and US Department of Energy Joint Genome Institute, Walnut Creek, California 94598, USA.
- Human Genetics Center and Institute for Molecular Medicine, University of Texas Health Science Center, Houston, Texas 77030, USA.
- Howard Hughes Medical Institute at the University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard Dallas, Texas 75390, USA.
- These authors contributed equally to this work.
Correspondence to: Helen H Hobbs1,7 e-mail: helen.hobbs@utsouthwestern.edu
Correspondence to: Jonathan C Cohen1 e-mail: jonathan.cohen@utsouthwestern.edu
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