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

Authors

Yuanbing Jiang, Hong Kong University of Science and Technology
Xiaopu Zhou, Hong Kong University of Science and Technology
Hiu Yi Wong, Hong Kong University of Science and Technology
Li Ouyang, Hong Kong University of Science and Technology
Fanny C.F. Ip, Hong Kong University of Science and Technology
Vicky M.N. Chau, Hong Kong University of Science and Technology
Shun Fat Lau, Hong Kong University of Science and Technology
Wei Wu, Hong Kong University of Science and Technology
Daniel Y.K. Wong, Hong Kong University of Science and Technology
Heukjin Seo, Hong Kong University of Science and Technology
Wing Yu Fu, Hong Kong University of Science and Technology
Nicole C.H. Lai, Hong Kong University of Science and Technology
Yuewen Chen, Hong Kong University of Science and Technology
Yu Chen, Hong Kong University of Science and Technology
Estella P.S. Tong, Hong Kong University of Science and Technology
Michael W. Weiner, University of California, San Francisco
Paul Aisen, University of California, San Diego
Ronald Petersen, Mayo Clinic
Clifford R. Jack, Mayo Clinic
William Jagust, University of California, Berkeley
John Q. Trojanowski, University of Pennsylvania
Arthur W. Toga, University of Southern California
Laurel Beckett, University of California, Davis
Robert C. Green, Brigham and Women's Hospital
Andrew J. Saykin, Indiana University Bloomington
John Morris, Washington University in St. Louis
Leslie M. Shaw, University of Pennsylvania
Zaven Khachaturian, University of California, Davis
Greg Sorensen, Siemens AG
Lew Kuller, University of Pittsburgh

Document Type

Article

Publication Date

7-1-2022

Journal

Nature Aging

Volume

2

Issue

7

First Page

616

Last Page

634

URL with Digital Object Identifier

10.1038/s43587-022-00241-9

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.