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Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction.
Palmer, Nicholette D; Kahali, Bratati; Kuppa, Annapurna; Chen, Yanhua; Du, Xiaomeng; Feitosa, Mary F; Bielak, Lawrence F; O'Connell, Jeffrey R; Musani, Solomon K; Guo, Xiuqing; Smith, Albert V; Ryan, Kathleen A; Eirksdottir, Gudny; Allison, Matthew A; Bowden, Donald W; Budoff, Matthew J; Carr, J Jeffrey; Chen, Yii-Der I; Taylor, Kent D; Correa, Adolfo; Crudup, Breland F; Halligan, Brian; Yang, Jian; Kardia, Sharon L R; Launer, Lenore J; Fu, Yi-Ping; Mosley, Thomas H; Norris, Jill M; Terry, James G; O'Donnell, Christopher J; Rotter, Jerome I; Wagenknecht, Lynne E; Gudnason, Vilmundur; Province, Michael A; Peyser, Patricia A; Speliotes, Elizabeth K.
Affiliation
  • Palmer ND; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
  • Kahali B; Centre for Brain Research, Indian Institute of Science, Bangalore, Karnataka, India.
  • Kuppa A; Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
  • Chen Y; Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
  • Du X; Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
  • Feitosa MF; Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
  • Bielak LF; Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
  • O'Connell JR; Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
  • Musani SK; Department of Endocrinology, Diabetes, and Nutrition, University of Maryland-Baltimore, Baltimore, MD, USA.
  • Guo X; Department of Medicine, University of Mississippi, Jackson, MS, USA.
  • Smith AV; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA.
  • Ryan KA; Icelandic Heart Association, Kopavogur, Iceland.
  • Eirksdottir G; Department of Endocrinology, Diabetes, and Nutrition, University of Maryland-Baltimore, Baltimore, MD, USA.
  • Allison MA; Icelandic Heart Association, Kopavogur, Iceland.
  • Bowden DW; Department of Family Medicine and Public Health, University of California, San Diego, CA, USA.
  • Budoff MJ; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
  • Carr JJ; Department of Internal Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
  • Chen YI; Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • Taylor KD; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA.
  • Correa A; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA.
  • Crudup BF; Department of Medicine, University of Mississippi, Jackson, MS, USA.
  • Halligan B; Department of Medicine, University of Mississippi, Jackson, MS, USA.
  • Yang J; Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
  • Kardia SLR; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
  • Launer LJ; Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
  • Fu YP; Laboratory of Epidemiology and Population Sciences, National Institute of Aging, Bethesda, MD, USA.
  • Mosley TH; Framingham Heart Study, NHLBI, NIH, Framingham, MA, USA.
  • Norris JM; Office of Biostatistics Research, NHLBI, NIH, Bethesda, MD, USA.
  • Terry JG; Department of Medicine, University of Mississippi, Jackson, MS, USA.
  • O'Donnell CJ; Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Rotter JI; Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • Wagenknecht LE; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
  • Gudnason V; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA.
  • Province MA; Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
  • Peyser PA; Icelandic Heart Association, Kopavogur, Iceland.
  • Speliotes EK; Department of Medicine, University of Iceland, Reykjavik 101, Iceland.
Hum Mol Genet ; 30(15): 1443-1456, 2021 07 09.
Article in En | MEDLINE | ID: mdl-33856023
ABSTRACT
Nonalcoholic 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 < 5.30 × 10-7); 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 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 nonalcoholic steatohepatitis; 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Apolipoproteins E / Non-alcoholic Fatty Liver Disease / Obesity Type of study: Etiology_studies / Prognostic_studies / Risk_factors_studies Limits: Humans Language: En Journal: Hum Mol Genet Journal subject: BIOLOGIA MOLECULAR / GENETICA MEDICA Year: 2021 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Apolipoproteins E / Non-alcoholic Fatty Liver Disease / Obesity Type of study: Etiology_studies / Prognostic_studies / Risk_factors_studies Limits: Humans Language: En Journal: Hum Mol Genet Journal subject: BIOLOGIA MOLECULAR / GENETICA MEDICA Year: 2021 Type: Article Affiliation country: United States