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 languageEnglish
Pages (from-to)616-634
Number of pages19
JournalNature Aging
Volume2
Issue number7
DOIs
StatePublished - Jul 2022

Bibliographical note

Funding Information:
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.

Funding Information:
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 .

Funding Information:
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.

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

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology
  • Neuroscience (miscellaneous)

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