Identifying differential regulatory control of APOE ɛ4 on African versus European haplotypes as potential therapeutic targets. Issue 10 (3rd January 2022)

• Record Type: Journal Article
• Authors: Nuytemans, Karen; Lipkin Vasquez, Marina; Wang, Liyong; Van Booven, Derek; Griswold, Antony J.; Rajabli, Farid; Celis, Katrina; Oron, Oded; Hofmann, Natalia; Rolati, Sophie; Garcia‐Serje, Catherine; Zhang, Shanshan; Jin, Fulai; Argenziano, Mariana; Grant, Struan F.A.; Chesi, Alessandra; Brown, Christopher D.; Young, Juan I.; Dykxhoorn, Derek M.; Pericak‐Vance, Margaret A.; Vance, Jeffery M.
• Is Part Of: Alzheimer's & dementia. Volume 18:Issue 10(2022)
• Page Start: 1930
• Page End: 1942
• Publication Date: 2022-01-03
• Subjects: ancestry -- apolipoprotein E -- massively parallel reporter assays -- promoter capture protective variant -- regulatory elements; Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.12534
• Languages: English
• ISSNs: 1552-5260

Abstract

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.