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

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.

• Authors: 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
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 30 Issue 15 Pg. 1443-1456 (07 09 2021) ISSN: 1460-2083 [Electronic] England
• PMID: 33856023 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• ApoE protein, human
• Apolipoproteins E
• Triglycerides
• Alanine Transaminase

Topics

• Alanine Transaminase
• Alleles
• Alzheimer Disease (genetics)
• Apolipoproteins E (genetics, metabolism)
• Databases, Genetic
• Exome (genetics)
• Gene Frequency (genetics)
• Genome-Wide Association Study (methods)
• Humans
• Liver
• Liver Cirrhosis (genetics)
• Myocardial Infarction (genetics)
• Non-alcoholic Fatty Liver Disease (genetics, metabolism)
• Obesity (genetics, metabolism)
• Phenotype
• Polymorphism, Single Nucleotide (genetics)
• Prognosis
• Risk Factors
• Triglycerides