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 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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Figure 1: Genome-wide scan of liver triglyceride content measured by proton magnetic resonance imaging in the Dallas Heart Study (n = 2,111).
Figure 2: Association between a sequence variant in PNPLA3 (rs738409) and hepatic triglyceride content.
Figure 3: Identification of a PNPLA3 allele (rs6006460, encoding S453I) associated with lower hepatic fat content in African Americans in the Dallas Heart Study.

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Acknowledgements

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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H.H.H., J.C.C., E.B., L.A.P. and D.C. conceived, designed and directed the study; J.K., S.R., C.X. and A.P. performed and interpreted the genetic analysis. All the authors approved the final manuscript and contributed critical revisions to its intellectual content.

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Correspondence to Jonathan C Cohen or Helen H Hobbs.

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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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