Author Identifier
Eleanor O'Brien
https://orcid.org/0000-0001-5145-7340
Tenielle Porter
https://orcid.org/0000-0002-7887-6622
Simon Laws
Document Type
Journal Article
Publication Title
Nature Aging
Publisher
Springer Nature
School
Ctentre for Precision Health / School of Medical and Health Sciences
RAS ID
44430
Funders
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 / Alzheimer's Disease Neuroimaging Initiative / Science and Industry Endowment Fund / Medical Research Council / Alzheimer's Society / 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 (31671047) / University Grants Committee (AoE/M-604/16) / Alzheimer’s Research UK / Research Grants Council, University Grants Committee (T13-605/18-W) / Dementia Collaborative Research Centres, Australia / Innovation and Technology Commission (INNOHK18SC01, ITCPD/17-9, MRP/042/18X) / State Government of Victoria / National Key Research and Development Program of China (2017YFE0190000, 2018YFE0203600) / Australian Alzheimer's Research Foundation / Yulgilbar Foundation / Shenzhen Knowledge Innovation Program (JCYJ20170413173717055, JCYJ20180507183642005)
Grant Number
NHMRC Number : APP1161706
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.
DOI
10.1038/s43587-022-00241-9
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
Jiang, Y., Zhou, X., Wong, H.Y. et al. (2022). An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer’s disease. Nature Aging, 2, 616–634.
https://doi.org/10.1038/s43587-022-00241-9