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Abstract Details
Allele Specific Variation at APOE Increases Non-alcoholic Fatty Liver Disease and Obesity but Decreases Risk of Alzheimer's Disease and Myocardial Infarction
Nicholette D Palmer1, Bratati Kahali23, Annapurna Kuppa3, Yanhua Chen3, Xiaomeng Du3, Mary F Feitosa4, Lawrence F Bielak5, Jeffrey R O'Connell6, Solomon K Musani7, Xiuqing Guo8, Albert V Smith9, Kathleen A Ryan6, Gudny Eirksdottir9, Matthew A Allison10, Donald W Bowden1, Matthew J Budoff11, J Jeffrey Carr12, Yii-Der I Chen8, Kent D Taylor8, Adolfo Correa7, Breland F Crudup7, Brian Halligan3, Jian Yang13, Sharon L R Kardia5, Lenore J Launer14, Yi-Ping Fu1516, Thomas H Mosley7, Jill M Norris17, James G Terry12, Christopher J O'Donnell1, Jerome I Rotter8, Lynne E Wagenknecht18, Vilmundur Gudnason919, Michael A Province4, Patricia A Peyser5, Elizabeth K Speliotes3
Author information
1Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
2Centre for Brain Research, Indian Institute of Science, Bangalore, India.
3Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
4Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
5Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
6Department of Endocrinology, Diabetes, and Nutrition, University of Maryland-Baltimore, Baltimore, MD, USA.
7Department of Medicine, University of Mississippi, Jackson, MS, USA.
8The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA.
9Icelandic Heart Association, Kopavogur, Iceland.
10Department of Family Medicine and Public Health, University of California, San Diego, CA, USA.
11Department of Internal Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
12Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN, USA.
13Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
14Laboratory of Epidemiology and Population Sciences, National Institute of Aging, Bethesda, MD, USA.
15Framingham Heart Study, NHLBI, NIH, Framingham, MA, USA.
16Office of Biostatistics Research, NHLBI, NIH, Bethesda, MD, USA.
17Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
18Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
19Department of Medicine, University of Iceland, Reykjavik 101, Iceland.
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P < 5.30x10-7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction (MI) and Alzheimer's disease (ad) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to non-alcoholic steatohepatitis (NASH); however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and ad at the exome level in the largest analysis to date.