An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer’s disease

doi:10.1038/s43587-022-00241-9

An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer’s disease

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Abstract

Changes in the levels of circulating proteins are associated with Alzheimer’s disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33–ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR–Cas9 genome editing identified rs1921622, a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622, demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622/sST2 regulates amyloid-beta (Aβ) pathology through the modulation of microglial activation and Aβ clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD.

Original language	English
Pages (from-to)	616-634
Number of pages	19
Journal	Nature Aging
Volume	2
Issue number	7
DOIs	https://doi.org/10.1038/s43587-022-00241-9
State	Published - Jul 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s).

Funding

This study was supported in part by the National Key R&D Program of China (2018YFE0203600 and 2017YFE0190000); the Hong Kong Research Grants Council Theme-based Research Scheme (T13-605/18-W); the Area of Excellence Scheme of the University Grants Committee (AoE/M-604/16); the Innovation and Technology Commission (ITCPD/17-9, MRP/042/18X and INNOHK18SC01); the National Natural Science Foundation of China (31671047); the Guangdong Provincial Key S&T Program (2018B030336001); the Guangdong Provincial Fund for Basic and Applied Basic Research (2019B1515130004); the Shenzhen Knowledge Innovation Program (JCYJ20180507183642005 and JCYJ20170413173717055); and the Chow Tai Fook Charity Foundation (CTFCF18SC01). Analyses in AIBL were supported through NHMRC (Australia) funding awarded to S.M.L. (APP1161706). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank P. Kwan, H. Mok, C. Y. Ling and R. M. N. Lo for coordinating the collection of clinical data. We also thank P. -O. Couraud (Institut national de la santé et de la recherche médicale) for providing advice on the cell line culturing. We thank J. K. Y. Lau, E. K. F. Tam, Y. Duan, A. Miranda, C. W. S. Kwong, X. Yang, H. Cao, J. Xu, A. S. L. Yuen and G. P. O. Chiu for their excellent technical assistance as well as other members of the Ip Laboratory for their many helpful discussions. We thank the SWDBB for providing brain tissue for this study. The SWDBB is part of the Brains for Dementia Research program, jointly funded by Alzheimer’s Research UK and Alzheimer’s Society and supported by BRACE (Bristol Research into Alzheimer’s and Care of the Elderly) and the MRC. We thank the AIBL study ( https://aibl.csiro.au/ ). The AIBL study is a consortium between the Commonwealth Scientific and Industrial Research Organisation (CSIRO), Edith Cowan University, The Florey Institute and Austin Health. Partial financial support was provided by the US Alzheimer’s Association, the Alzheimer’s Drug Discovery Foundation, an anonymous foundation, the Cooperative Research Centre for Mental Health, the CSIRO Science and Industry Endowment Fund, the Dementia Collaborative Research Centres, the Victorian Government Operational Infrastructure Support program, the Australian Alzheimer’s Research Foundation, the National Health and MRC and the Yulgilbar Foundation. We also thank M. Vacher for providing advice on the data analysis. Please refer to the for corresponding acknowledgments for the ADNI dataset, Alzheimer’s Disease Genetics Consortium GWAS–NIA Alzheimer’s Disease Centers Cohort (ADC dataset), the NIA–LOAD dataset and the GTEx Project. Part of the data used in the preparation of this article was obtained from the ADNI database. As such, the investigators within ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found in the and at http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf . We thank P. Kwan, H. Mok, C. Y. Ling and R. M. N. Lo for coordinating the collection of clinical data. We also thank P. -O. Couraud (Institut national de la santé et de la recherche médicale) for providing advice on the cell line culturing. We thank J. K. Y. Lau, E. K. F. Tam, Y. Duan, A. Miranda, C. W. S. Kwong, X. Yang, H. Cao, J. Xu, A. S. L. Yuen and G. P. O. Chiu for their excellent technical assistance as well as other members of the Ip Laboratory for their many helpful discussions. We thank the SWDBB for providing brain tissue for this study. The SWDBB is part of the Brains for Dementia Research program, jointly funded by Alzheimer’s Research UK and Alzheimer’s Society and supported by BRACE (Bristol Research into Alzheimer’s and Care of the Elderly) and the MRC. We thank the AIBL study (https://aibl.csiro.au/). The AIBL study is a consortium between the Commonwealth Scientific and Industrial Research Organisation (CSIRO), Edith Cowan University, The Florey Institute and Austin Health. Partial financial support was provided by the US Alzheimer’s Association, the Alzheimer’s Drug Discovery Foundation, an anonymous foundation, the Cooperative Research Centre for Mental Health, the CSIRO Science and Industry Endowment Fund, the Dementia Collaborative Research Centres, the Victorian Government Operational Infrastructure Support program, the Australian Alzheimer’s Research Foundation, the National Health and MRC and the Yulgilbar Foundation. We also thank M. Vacher for providing advice on the data analysis. Please refer to the Supplementary Notes for corresponding acknowledgments for the ADNI dataset, Alzheimer’s Disease Genetics Consortium GWAS–NIA Alzheimer’s Disease Centers Cohort (ADC dataset), the NIA–LOAD dataset and the GTEx Project. Part of the data used in the preparation of this article was obtained from the ADNI database. As such, the investigators within ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found in the Supplementary Notes and at http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf. This study was supported in part by the National Key R&D Program of China (2018YFE0203600 and 2017YFE0190000); the Hong Kong Research Grants Council Theme-based Research Scheme (T13-605/18-W); the Area of Excellence Scheme of the University Grants Committee (AoE/M-604/16); the Innovation and Technology Commission (ITCPD/17-9, MRP/042/18X and INNOHK18SC01); the National Natural Science Foundation of China (31671047); the Guangdong Provincial Key S&T Program (2018B030336001); the Guangdong Provincial Fund for Basic and Applied Basic Research (2019B1515130004); the Shenzhen Knowledge Innovation Program (JCYJ20180507183642005 and JCYJ20170413173717055); and the Chow Tai Fook Charity Foundation (CTFCF18SC01). Analyses in AIBL were supported through NHMRC (Australia) funding awarded to S.M.L. (APP1161706). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

Funders	Funder number
Bristol Research into Alzheimer’s and Care of the Elderly
Chow Tai Fook Charity Foundation	CTFCF18SC01
Cooperative Research Centre for Mental Health
GTEx
Guangdong Provincial Fund for Basic and Applied Basic Research	2019B1515130004
Guangdong Provincial Key S&T Program	2018B030336001
National Health and MRC
National Institute on Aging
Alzheimer's Association
Alzheimer's Drug Discovery Foundation
DoD Alzheimer's Disease Neuroimaging Initiative
Science and Industry Endowment Fund
Medical Research Council
Alzheimer's Society
Australian National Health and Medical Research Council	APP1161706
Australian National Health and Medical Research Council
Commonwealth Scientific and Industrial Research Organisation
Institut national de la santé et de la recherche médicale
Edith Cowan University
National Natural Science Foundation of China (NSFC)	31671047
National Natural Science Foundation of China (NSFC)
Research Grants Council, University Grants Committee	AoE/M-604/16
Research Grants Council, University Grants Committee
Alzheimer’s Research United Kingdom
Research Grants Council, University Grants Committee	T13-605/18-W
Research Grants Council, University Grants Committee
Dementia Collaborative Research Centres, Australia
Innovation and Technology Commission	INNOHK18SC01, ITCPD/17-9, MRP/042/18X
Innovation and Technology Commission
State Government of Victoria
National Key Basic Research and Development Program of China	2017YFE0190000, 2018YFE0203600
National Key Basic Research and Development Program of China
Australian Alzheimer's Research Foundation
Yulgilbar Foundation
Shenzhen Knowledge Innovation Program	JCYJ20180507183642005, JCYJ20170413173717055
Shenzhen Knowledge Innovation Program

ASJC Scopus subject areas

Geriatrics and Gerontology
Aging
Neuroscience (miscellaneous)

UN SDGs

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

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10.1038/s43587-022-00241-9

Cite this

@article{6c09db22227a438088fd1ca0bd6bf315,

title = "An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer{\textquoteright}s disease",

abstract = "Changes in the levels of circulating proteins are associated with Alzheimer{\textquoteright}s disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33–ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR–Cas9 genome editing identified rs1921622, a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622, demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622/sST2 regulates amyloid-beta (Aβ) pathology through the modulation of microglial activation and Aβ clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD.",

author = "Yuanbing Jiang and Xiaopu Zhou and Wong, {Hiu Yi} and Li Ouyang and Ip, {Fanny C.F.} and Chau, {Vicky M.N.} and Lau, {Shun Fat} and Wei Wu and Wong, {Daniel Y.K.} and Heukjin Seo and Fu, {Wing Yu} and Lai, {Nicole C.H.} and Yuewen Chen and Yu Chen and Tong, {Estella P.S.} and Weiner, {Michael W.} and Paul Aisen and Ronald Petersen and Jack, {Clifford R.} and William Jagust and Trojanowski, {John Q.} and Toga, {Arthur W.} and Laurel Beckett and Green, {Robert C.} and Saykin, {Andrew J.} and John Morris and Shaw, {Leslie M.} and Zaven Khachaturian and Greg Sorensen and Lew Kuller and Marcus Raichle and Steven Paul and Peter Davies and Howard Fillit and Franz Hefti and David Holtzman and Mesulam, {Marek M.} and William Potter and Peter Snyder and Adam Schwartz and Tom Montine and Thomas, {Ronald G.} and Michael Donohue and Sarah Walter and Devon Gessert and Tamie Sather and Gus Jiminez and Danielle Harvey and Greg Jicha and Richard King",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

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doi = "10.1038/s43587-022-00241-9",

language = "English",

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AU - Toga, Arthur W.

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AU - Green, Robert C.

AU - Saykin, Andrew J.

AU - Morris, John

AU - Shaw, Leslie M.

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AU - Sorensen, Greg

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AU - Raichle, Marcus

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AU - King, Richard

PY - 2022/7

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N2 - Changes in the levels of circulating proteins are associated with Alzheimer’s disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33–ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR–Cas9 genome editing identified rs1921622, a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622, demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622/sST2 regulates amyloid-beta (Aβ) pathology through the modulation of microglial activation and Aβ clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD.

AB - Changes in the levels of circulating proteins are associated with Alzheimer’s disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33–ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR–Cas9 genome editing identified rs1921622, a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622, demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622/sST2 regulates amyloid-beta (Aβ) pathology through the modulation of microglial activation and Aβ clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD.

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An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer’s disease

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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