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.
We previously demonstrated that in Alzheimer’s disease (AD)
patients, European apolipoprotein E (
APOE
)
ε
4 carriers express significantly more
APOEε
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 ε
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 ε
4 carriers.
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