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Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.

Artikel i vetenskaplig tidskrift
Författare Elizabeth K Speliotes
Laura M Yerges-Armstrong
Jun Wu
Ruben Hernaez
Lauren J Kim
Cameron D Palmer
Vilmundur Gudnason
Gudny Eiriksdottir
Melissa E Garcia
Lenore J Launer
Michael A Nalls
Jeanne M Clark
Braxton D Mitchell
Alan R Shuldiner
Johannah L Butler
Marta Tomas
Udo Hoffmann
Shih-Jen Hwang
Joseph M Massaro
Christopher J O'Donnell
Dushyant V Sahani
Veikko Salomaa
Eric E Schadt
Stephen M Schwartz
David S Siscovick
(NASH CRN) NASH Clinical Research Network
Consortium Giant
Investigators MAGIC
Benjamin F Voight
J Jeffrey Carr
Mary F Feitosa
Tamara B Harris
Caroline S Fox
Albert V Smith
W H Linda Kao
Joel N Hirschhorn
Ingrid B Borecki
Consortium GOLD
John-Olov Jansson
Publicerad i PLoS genetics
Volym 7
Nummer/häfte 3
Sidor e1001324
ISSN 1553-7404
Publiceringsår 2011
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi
Sidor e1001324
Språk en
Länkar dx.doi.org/10.1371/journal.pgen.100...
Ämneskategorier Medicin och Hälsovetenskap

Sammanfattning

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.

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