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

  1. Donald W. Reynolds Cardiovascular Clinical Research Center, Eugene McDermott Center for Human Growth and Development, 6000 Harry Hines Boulevard Dallas, Texas 75390, USA.
  2. Department of Clinical Sciences, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard Dallas, Texas 75390, USA.
  3. Department of Statistical Science, Southern Methodist University, Dallas, Texas 75275, USA.
  4. Perlegen Sciences, Mountain View, California 94043, USA.
  5. Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720 and US 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, USA.
  8. 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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