期刊
NATURE GENETICS
卷 40, 期 12, 页码 1461-1465出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.257
关键词
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资金
- Donald W. Reynolds Foundation
- US National Institutes of Health [RL1HL-092550, 1PL1DK081182, HL-20948]
- US National Heart, Lung, and Blood Institute (NHLBI) Program for Genomic Applications [HL-066681]
- US Department of Energy [DE-AC02-05CH11231]
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 x 10(-10)) and with hepatic inflammation (P = 3.7 x 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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