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Palmer ND, Kahali B, Kuppa A, et al. Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction. Hum Mol Genet. 2021;30(15):1443-1456doi: 10.1093/hmg/ddab096.
Palmer, N. D., Kahali, B., Kuppa, A., Chen, Y., Du, X., Feitosa, M. F., Bielak, L. F., O'Connell, J. R., Musani, S. K., Guo, X., Smith, A. V., Ryan, K. A., Eirksdottir, G., Allison, M. A., Bowden, D. W., Budoff, M. J., Carr, J. J., Chen, Y. I., Taylor, K. D., Correa, A., Crudup, B. F., Halligan, B., Yang, J., Kardia, S. L. R., Launer, L. J., Fu, Y. P., Mosley, T. H., Norris, J. M., Terry, J. G., O'Donnell, C. J., Rotter, J. I., Wagenknecht, L. E., Gudnason, V., Province, M. A., Peyser, P. A., & Speliotes, E. K. (2021). Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction. Human molecular genetics, 30(15), 1443-1456. https://doi.org/10.1093/hmg/ddab096
Palmer, Nicholette D, et al. "Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction." Human molecular genetics vol. 30,15 (2021): 1443-1456. doi: https://doi.org/10.1093/hmg/ddab096
Palmer ND, Kahali B, Kuppa A, Chen Y, Du X, Feitosa MF, Bielak LF, O'Connell JR, Musani SK, Guo X, Smith AV, Ryan KA, Eirksdottir G, Allison MA, Bowden DW, Budoff MJ, Carr JJ, Chen YI, Taylor KD, Correa A, Crudup BF, Halligan B, Yang J, Kardia SLR, Launer LJ, Fu YP, Mosley TH, Norris JM, Terry JG, O'Donnell CJ, Rotter JI, Wagenknecht LE, Gudnason V, Province MA, Peyser PA, Speliotes EK. Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction. Hum Mol Genet. 2021 Jul 09;30(15):1443-1456. doi: 10.1093/hmg/ddab096. PMID: 33856023; PMCID: PMC8283205.
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Hum Mol Genet. 2021 Jul 09;30(15):1443-1456. doi: 10.1093/hmg/ddab096.

Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction.

Human molecular genetics

Nicholette D Palmer, Bratati Kahali, Annapurna Kuppa, Yanhua Chen, Xiaomeng Du, Mary F Feitosa, Lawrence F Bielak, Jeffrey R O'Connell, Solomon K Musani, Xiuqing Guo, Albert V Smith, Kathleen A Ryan, Gudny Eirksdottir, Matthew A Allison, Donald W Bowden, Matthew J Budoff, J Jeffrey Carr, Yii-Der I Chen, Kent D Taylor, Adolfo Correa, Breland F Crudup, Brian Halligan, Jian Yang, Sharon L R Kardia, Lenore J Launer, Yi-Ping Fu, Thomas H Mosley, Jill M Norris, James G Terry, Christopher J O'Donnell, Jerome I Rotter, Lynne E Wagenknecht, Vilmundur Gudnason, Michael A Province, Patricia A Peyser, Elizabeth K Speliotes

Affiliations

  1. Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
  2. Centre for Brain Research, Indian Institute of Science, Bangalore, Karnataka, India.
  3. Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
  4. Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
  5. Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
  6. Department of Endocrinology, Diabetes, and Nutrition, University of Maryland-Baltimore, Baltimore, MD, USA.
  7. Department of Medicine, University of Mississippi, Jackson, MS, USA.
  8. 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.
  9. Icelandic Heart Association, Kopavogur, Iceland.
  10. Department of Family Medicine and Public Health, University of California, San Diego, CA, USA.
  11. Department of Internal Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
  12. Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN, USA.
  13. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
  14. Laboratory of Epidemiology and Population Sciences, National Institute of Aging, Bethesda, MD, USA.
  15. Framingham Heart Study, NHLBI, NIH, Framingham, MA, USA.
  16. Office of Biostatistics Research, NHLBI, NIH, Bethesda, MD, USA.
  17. Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  18. Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
  19. Department of Medicine, University of Iceland, Reykjavik 101, Iceland.

PMID: 33856023 PMCID: PMC8283205 DOI: 10.1093/hmg/ddab096

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.

© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

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