@article{f093e46b5bb9432b888193c36985ab05,
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 = "{Alzheimer{\textquoteright}s Disease Neuroimaging Initiative} and 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 Matthew Bernstein and Hillel Grossman",
note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = jul,
doi = "10.1038/s43587-022-00241-9",
language = "English",
volume = "2",
pages = "616--634",
journal = "Nature Aging",
issn = "2662-8465",
publisher = "Springer",
number = "7",
}