Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits
Elizabeth K. Speliotes,Laura M. Yerges-Armstrong,Jun Wu,Ruben Hernaez,Ruben Hernaez,Lauren J. Kim,Cameron D. Palmer,Vilmundur Gudnason,Gudny Eiriksdottir,Melissa E. Garcia,Lenore J. Launer,Mike A. Nalls,Jeanne M. Clark,Braxton D. Mitchell,Alan R. Shuldiner,Alan R. Shuldiner,Johannah L. Butler,Johannah L. Butler,Marta Tomas,Udo Hoffmann,Shih-Jen Hwang,Joseph M. Massaro,Joseph M. Massaro,Christopher J. O'Donnell,Christopher J. O'Donnell,Dushyant V. Sahani,Veikko Salomaa,Eric E. Schadt,Stephen M. Schwartz,David S. Siscovick,Nash Crn,Magic Investigators,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,Joel N. Hirschhorn,Joel N. Hirschhorn,Ingrid B. Borecki +42 more
TLDR
In this article, 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 (n = 880 to 3,070).Abstract:
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,5610 28 ) 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.read more
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Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.
TL;DR: Aliment Pharmacol Ther 2011; 34: 274–285
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Human fatty liver disease: old questions and new insights.
TL;DR: Recent mechanistic insights into nonalcoholic fatty liver disease are discussed, focusing primarily on those that have emerged from human genetic and metabolic studies.
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MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease.
TL;DR: Experts reached consensus that NAFLD does not reflect current knowledge and metabolic (dysfunction) associated fatty liver disease "MAFLD" was suggested as a more appropriate overarching term and opens the door for efforts from the research community to update the nomenclature and sub-phenotype the disease in order to accelerate the translational path to new treatments.
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The global NAFLD epidemic
Rohit Loomba,Arun J. Sanyal +1 more
TL;DR: The similarities and differences in the epidemiology of NAFLD in different regions of the world are discussed and the potential role of genetics and insulin resistance in disease progression is also presented.
Journal ArticleDOI
Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis.
TL;DR: The evidence that suggests NAFLD is a multisystem disease and the factors that might determine interindividual variation in the development and progression of its major hepatic and extrahepatic manifestations are reviewed.
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Laura Almasy,John Blangero +1 more
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