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Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease

Goran, Michael I.; Walker, Ryan; Le, Kim Anne; Mahurkar, Swapna; Vikman, Susanna; Davis, Jaimie N.; Spruijt-Metz, Donna; Weigensberg, Marc J.; Allayee, Hooman; Romeo, Stefano; Kozlitina, Julia; Xing, Chao; Pertsemlidis, Alexander; Cox, David; Pennacchio, Len A.; Boerwinkle, Eric; Cohen, Jonathan C.; Hobbs, Helen H.

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2008

10.1038/ng.257

ISBN: 1546-1718 (Electronic)$\backslash$n1061-4036 (Linking) PMID: 18820647

Abstract:

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem of unknown etiology that varies in prevalence among ethnic groups. To identify genetic variants contributing to differences in hepatic fat content, we performed a genome-wide association scan of nonsynonymous sequence variations (n=9,229) in a multiethnic population. An allele in PNPLA3 (rs738409; 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 \textgreater 2-fold higher in PNPLA3-148M homozygotes than in noncarriers. Resequencing revealed another allele associated with lower hepatic fat content in African-Americans, the group at lowest risk of NAFLD. Thus, variation in PNPLA3 contributes to ethnic and inter-individual differences in hepatic fat content and susceptibility to NAFLD.