Identifying differential regulatory control of APOE ɛP on African versus European haplotypes as potential therapeutic targets

Karen Nuytemans, Marina Lipkin Vasquez, Liyong Wang, Derek Van Booven, Antony J. Griswold, Farid Rajabli, Katrina Celis, Oded Oron, Natalia Hofmann, Sophie Rolati, Catherine Garcia-Serje, Shanshan Zhang, Fulai Jin, Mariana Argenziano, Struan F.A. Grant, Alessandra Chesi, Christopher D. Brown, Juan I. Young, Derek M. Dykxhoorn, Margaret A. Pericak-VanceJeffery M. Vance

Research output: Contribution to journalArticlepeer-review

Abstract

We previously demonstrated that in Alzheimer's disease (AD) patients, European apolipoprotein E (APOE) ε4 carriers express significantly more APOE ε4 in their brains than African AD carriers. We examined single nucleotide polymorphisms near APOE with significant frequency differences between African and European/Japanese APOE ε4 haplotypes that could contribute to this difference in expression through regulation. Two enhancer massively parallel reporter assay (MPRA) approaches were performed, supplemented with single fragment reporter assays. We used Capture C analyses to support interactions with the APOE promoter. Introns within TOMM40 showed increased enhancer activity in the European/Japanese versus African haplotypes in astrocytes and microglia. This region overlaps with APOE promoter interactions as assessed by Capture C analysis. Single variant analyses pinpoints rs2075650/rs157581, and rs59007384 as functionally different on these haplotypes. Identification of the mechanisms for differential regulatory function for APOE expression between African and European/Japanese haplotypes could lead to therapeutic targets for APOE ε4 carriers.

Original languageEnglish (US)
JournalAlzheimer's and Dementia
DOIs
StateAccepted/In press - 2022
Externally publishedYes

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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