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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.

TitleAllele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction.
Publication TypeJournal Article
Year of Publication2021
AuthorsPalmer 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, J Carr J, Chen Y-DI, Taylor KD, Correa A, Crudup BF, Halligan B, Yang J, Kardia SLR, Launer LJ, Fu Y-P, Mosley TH, Norris JM, Terry JG, O'Donnell CJ, Rotter JI, Wagenknecht LE, Gudnason V, Province MA, Peyser PA, Speliotes EK
JournalHum Mol Genet
Volume30
Issue15
Pagination1443-1456
Date Published2021 Jul 09
ISSN1460-2083
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.

DOI10.1093/hmg/ddab096
Alternate JournalHum Mol Genet
PubMed ID33856023
PubMed Central IDPMC8283205
Grant ListUL1TR001881 / TR / NCATS NIH HHS / United States
U01 AG009740 / AG / NIA NIH HHS / United States
UL1-TR-001420 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
RC2 AG036495 / AG / NIA NIH HHS / United States
HHSN271201100004C / AG / NIA NIH HHS / United States
R01 DK089256 / DK / NIDDK NIH HHS / United States
UL1 TR001881 / TR / NCATS NIH HHS / United States
R01 DK085175 / DK / NIDDK NIH HHS / United States
HHSN268201800012I / / University of Mississippi Medical Center /
/ / Department of Internal Medicine, University of Nebraska Medical Center /
/ / Hjartavernd /
HHSN268201100046C / HL / NHLBI NIH HHS / United States
RO1 DK107904 / NH / NIH HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
R01 HL117078 / HL / NHLBI NIH HHS / United States
DK085175 / DK / NIDDK NIH HHS / United States
HHSN268201800013I / MD / NIMHD NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
HHSN268201800015I / HB / NHLBI NIH HHS / United States
DK063491 / / Diabetes Research Center /
7-07-MN-08 / / American Diabetes Association Mentor-Based Postdoctoral Fellowship Program /