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.
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Wang, M.Y. et al. Adipogenic capacity and the susceptibility to type 2 diabetes and metabolic syndrome. Proc. Natl. Acad. Sci. USA 105, 6139–6144 (2008).
Browning, J.D. et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40, 1387–1395 (2004).
Browning, J.D. & Horton, J.D. Molecular mediators of hepatic steatosis and liver injury. J. Clin. Invest. 114, 147–152 (2004).
McCullough, A.J. The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clin. Liver Dis. 8, 521–533 (2004).
Adams, L.A. et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129, 113–121 (2005).
de Alwis, N.M. & Day, C.P. Non-alcoholic fatty liver disease: the mist gradually clears. J. Hepatol. 48 (Suppl. 1), S104–S112 (2008).
Browning, J.D., Kumar, K.S., Saboorian, M.H. & Thiele, D.L. Ethnic differences in the prevalence of cryptogenic cirrhosis. Am. J. Gastroenterol. 99, 292–298 (2004).
Clark, J.M., Brancati, F.L. & Diehl, A.M. The prevalence and etiology of elevated aminotransferase levels in the United States. Am. J. Gastroenterol. 98, 960–967 (2003).
Caldwell, S.H., Harris, D.M., Patrie, J.T. & Hespenheide, E.E. Is NASH underdiagnosed among African Americans? Am. J. Gastroenterol. 97, 1496–1500 (2002).
Victor, R.G. et al. The Dallas Heart Study: a population-based probability sample for the multidisciplinary study of ethnic differences in cardiovascular health. Am. J. Cardiol. 93, 1473–1480 (2004).
Longo, R. et al. Proton MR spectroscopy in quantitative in vivo determination of fat content in human liver steatosis. J. Magn. Reson. Imaging 5, 281–285 (1995).
Szczepaniak, L.S. et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am. J. Physiol. Endocrinol. Metab. 288, E462–E468 (2005).
Hinds, D.A. et al. Whole-genome patterns of common DNA variation in three human populations. Science 307, 1072–1079 (2005).
Wilson, P.A., Gardner, S.D., Lambie, N.M., Commans, S.A. & Crowther, D.J. Characterization of the human patatin-like phospholipase family. J. Lipid Res. 47, 1940–1948 (2006).
Rydel, T.J. et al. The crystal structure, mutagenesis, and activity studies reveal that patatin is a lipid acyl hydrolase with a ser-asp catalytic dyad. Biochemistry 42, 6696–6708 (2003).
Strickland, J.A., Orr, G.L. & Walsh, T.A. Inhibition of Diabrotica larval growth by patatin, the lipid acyl hydrolase from potato tubers. Plant Physiol. 109, 667–674 (1995).
National Heart, Lung, and Blood Institute. Atherosclerosis Risk in Communities (ARIC) Study. Operations Manual No 2: Cohort Component Procedures. (ARIC Coordinating Center, School of Public Health, University of North Carolina, Chapel Hill, North Carolina, 1987).
Minehira, K. et al. Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice. J. Lipid Res. 49, 2038–2044 (2008).
Monetti, M. et al. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab. 6, 69–78 (2007).
Baulande, S., Lassnier, F., Lucas, M. & Pairault, J. Adiponutrin, a transmembrane protein corresponding to a novel dietary- and obesity-linked mRNA specifically expressed in the adipose lineage. J. Biol. Chem. 276, 33336–33344 (2001).
Lake, A.C. et al. Expression, regulation, and triglyceride hydrolase activity of adiponutrin family members. J. Lipid Res. 46, 2477–2487 (2005).
Jenkins, C.M. et al. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J. Biol. Chem. 279, 48968–48975 (2004).
Yuan, X. et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am. J. Hum. Genet. (in the press).
Rietz, S., Holk, A. & Scherer, G.F. Expression of the patatin-related phospholipase A gene AtPLA IIA in Arabidopsis thaliana is up-regulated by salicylic acid, wounding, ethylene, and iron and phosphate deficiency. Planta 219, 743–753 (2004).
Brown, S.A. et al. Plasma lipid, lipoprotein cholesterol, and apoprotein distributions in selected U.S. communities. Arterioscler. Thromb. 13, 1139–1158 (1993).
Falush, D., Stephens, M. & Pritchard, J.K. Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. Genetics 164, 1567–1587 (2003).
Smith, M.W. et al. A high-density admixture map for disease gene discovery in African Americans. Am. J. Hum. Genet. 74, 1001–1013 (2004).
Zhu, X. et al. Admixture mapping for hypertension loci with genome-scan markers. Nat. Genet. 37, 177–181 (2005).
Romeo, S. et al. Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat. Genet. 39, 513–516 (2007).
We thank T. Hyatt, J. Martin, W. Schackwitz, A. Ustaszewska, C. Wright and the team at Perlegen Sciences for technical assistance. We thank K. Lawson for the statistical analysis of the data from the ARIC study. We thank J. Horton and D. Hinds for helpful discussions. We are grateful to the staff and participants of the Dallas Heart Study and the Atherosclerosis Risk in Communities Study for their contributions. This work was supported by grants from the Donald W. Reynolds Foundation, the US National Institutes of Health (RL1HL-092550, 1PL1DK081182 and HL-20948), the US National Heart, Lung, and Blood Institute (NHLBI) Program for Genomic Applications (HL-066681) and the US Department of Energy (Contract DE-AC02-05CH11231).
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Romeo, S., Kozlitina, J., Xing, C. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 40, 1461–1465 (2008). https://doi.org/10.1038/ng.257
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