Identifying differential regulatory control of APOE ɛ4 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-Vance; Jeffery M. Vance

doi:10.1002/alz.12534

Identifying differential regulatory control of APOE ɛ4 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 journal › Article › peer-review

14 Scopus citations

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 language	English
Pages (from-to)	1930-1942
Number of pages	13
Journal	Alzheimer's and Dementia
Volume	18
Issue number	10
DOIs	https://doi.org/10.1002/alz.12534
State	Published - Oct 2022
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2021 the Alzheimer's Association.

Funding

We thank Dr. Ryan Tewhey for consulting on the probe‐based MPRA library creation. This research was supported by the National Institute on Aging (AG059018 – PI JV; KN, MLV, LW, AG, KC, OO, JY, DD‐, AG054074 – PI MP; LW, AG, NH, SR, DD, CGS, FR, DB, JV‐, AG072547 – PI MP; JV‐, AG057659 – PI MP, HG009658‐ PI FJ; SZ‐, AG057516 – PI SG; MA, AC‐) as well as Alzheimer Association (ZEN‐19‐591585‐ PI JV; KN, MLV, LW, KC, OO, JY, DD) and BrightFocus (A2018425S – PI JV; KN, LW, AG, FR, JY). We thank Dr. Ryan Tewhey for consulting on the probe-based MPRA library creation. This research was supported by the National Institute on Aging (AG059018 – PI JV; KN, MLV, LW, AG, KC, OO, JY, DD-, AG054074 – PI MP; LW, AG, NH, SR, DD, CGS, FR, DB, JV-, AG072547 – PI MP; JV-, AG057659 – PI MP, HG009658- PI FJ; SZ-, AG057516 – PI SG; MA, AC-) as well as Alzheimer Association (ZEN-19-591585- PI JV; KN, MLV, LW, KC, OO, JY, DD) and BrightFocus (A2018425S – PI JV; KN, LW, AG, FR, JY). Authors further disclosure support from NIH (KN, LW, FR, SG, AG, JY, CB, DD, MP, JV), State of Florida grants (KN, AG, JY, DMD), Miami Heart Research Institute (LW), Helping Hands for GAND Foundation (JY). Royalties have been received by JV (Duke University) and JY (Elsevier). Consulting fees have been received by AG (Northwestern University) and JV (University of Pennsylvania). SG receives funds from patents (US Patent Number 10,125,395, 2018; US Patent Number 9,926,600, 2018; US Patent Number 10,066,266, 2018; Canada Patent Number 2,714,713, 2018; US Patent Number 10,266,896, 2019). JY has contributed to the Helping Hands for GAND Foundation scientific advisory board without compensation. ML, DVB, KC, OO, NH, and SR declare no further disclosures.

Funders	Funder number
Helping Hands for GAND Foundation
Miami Heart Research Institute
State of Florida
National Institutes of Health
National Institute on Aging	U01AG057659, AG054074, HG009658, AG057516, AG059018, AG072547
Alzheimer's Association	ZEN-19-591585

Keywords

ancestry
apolipoprotein E
massively parallel reporter assays
promoter capture protective variant
regulatory elements

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/alz.12534

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Nuytemans, K., Lipkin Vasquez, M., Wang, L., Van Booven, D., Griswold, A. J., Rajabli, F., Celis, K., Oron, O., Hofmann, N., Rolati, S., Garcia-Serje, C., Zhang, S., Jin, F., Argenziano, M., Grant, S. F. A., Chesi, A., Brown, C. D., Young, J. I., Dykxhoorn, D. M., ... Vance, J. M. (2022). Identifying differential regulatory control of APOE ɛ4 on African versus European haplotypes as potential therapeutic targets. Alzheimer's and Dementia, 18(10), 1930-1942. https://doi.org/10.1002/alz.12534

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title = "Identifying differential regulatory control of APOE ɛ4 on African versus European haplotypes as potential therapeutic targets",

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.",

keywords = "ancestry, apolipoprotein E, massively parallel reporter assays, promoter capture protective variant, regulatory elements",

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

note = "Publisher Copyright: {\textcopyright} 2021 the Alzheimer's Association.",

year = "2022",

month = oct,

doi = "10.1002/alz.12534",

language = "אנגלית",

volume = "18",

pages = "1930--1942",

journal = "Alzheimer's and Dementia",

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Nuytemans, K, Lipkin Vasquez, M, Wang, L, Van Booven, D, Griswold, AJ, Rajabli, F, Celis, K, Oron, O, Hofmann, N, Rolati, S, Garcia-Serje, C, Zhang, S, Jin, F, Argenziano, M, Grant, SFA, Chesi, A, Brown, CD, Young, JI, Dykxhoorn, DM, Pericak-Vance, MA & Vance, JM 2022, 'Identifying differential regulatory control of APOE ɛ4 on African versus European haplotypes as potential therapeutic targets', Alzheimer's and Dementia, vol. 18, no. 10, pp. 1930-1942. https://doi.org/10.1002/alz.12534

TY - JOUR

T1 - Identifying differential regulatory control of APOE ɛ4 on African versus European haplotypes as potential therapeutic targets

AU - Nuytemans, Karen

AU - Lipkin Vasquez, Marina

AU - Wang, Liyong

AU - Van Booven, Derek

AU - Griswold, Antony J.

AU - Rajabli, Farid

AU - Celis, Katrina

AU - Oron, Oded

AU - Hofmann, Natalia

AU - Rolati, Sophie

AU - Garcia-Serje, Catherine

AU - Zhang, Shanshan

AU - Jin, Fulai

AU - Argenziano, Mariana

AU - Grant, Struan F.A.

AU - Chesi, Alessandra

AU - Brown, Christopher D.

AU - Young, Juan I.

AU - Dykxhoorn, Derek M.

AU - Pericak-Vance, Margaret A.

AU - Vance, Jeffery M.

PY - 2022/10

Y1 - 2022/10

N2 - 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.

AB - 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.

KW - ancestry

KW - apolipoprotein E

KW - massively parallel reporter assays

KW - promoter capture protective variant

KW - regulatory elements

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DO - 10.1002/alz.12534

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AN - SCOPUS:85122179285

SN - 1552-5260

VL - 18

SP - 1930

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JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 10

ER -

Identifying differential regulatory control of APOE ɛ4 on African versus European haplotypes as potential therapeutic targets

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

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Cite this