Identifying differential regulatory control of APOE eP on African versus European haplotypes as potential therapeutic targets
ALZHEIMERS & DEMENTIA(2022)
摘要
We previously demonstrated that in Alzheimer's disease (AD) patients, European apolipoprotein E (APOE) epsilon 4 carriers express significantly more APOE epsilon 4 in their brains than African AD carriers. We examined single nucleotide polymorphisms near APOE with significant frequency differences between African and European/Japanese APOE epsilon 4 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 epsilon 4 carriers.
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关键词
ancestry,apolipoprotein E,massively parallel reporter assays,promoter capture protective variant,regulatory elements
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