@article{04947a4cb2734fa4ab807247052cdbc7,
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 Paul Thompson and Norbert Schuff and Bret Borowski and Jeff Gunter and Matt Senjem and Prashanthi Vemuri and David Jones and Kejal Kantarci and Chad Ward and Koeppe, {Robert A.} and Norm Foster and Reiman, {Eric M.} and Kewei Chen and Chet Mathis and Susan Landau and Cairns, {Nigel J.} and Erin Householder and Lisa Taylor-Reinwald and Virginia Lee and Magdalena Korecka and Michal Figurski and Karen Crawford and Scott Neu and Foroud, {Tatiana M.} and Potkin, {Steven G.} and Li Shen and Kelley Faber and Sungeun Kim and Kwangsik Nho and Leon Thal and Neil Buckholtz and Marylyn Albert and Richard Frank and John Hsiao and Jeffrey Kaye and Joseph Quinn and Betty Lind and Raina Carter and Sara Dolen and Schneider, {Lon S.} and Sonia Pawluczyk and Mauricio Beccera and Liberty Teodoro and Spann, {Bryan M.} and James Brewer and Helen Vanderswag and Adam Fleisher and Heidebrink, {Judith L.} and Lord, {Joanne L.} and Mason, {Sara S.} and Albers, {Colleen S.} and David Knopman and Kris Johnson and Doody, {Rachelle S.} and Javier Villanueva-Meyer and Munir Chowdhury and Susan Rountree and Mimi Dang and Yaakov Stern and Honig, {Lawrence S.} and Bell, {Karen L.} and Beau Ances and Maria Carroll and Sue Leon and Mintun, {Mark A.} and Stacy Schneider and Angela Oliver and Daniel Marson and Randall Griffith and David Clark and David Geldmacher and John Brockington and Erik Roberson and Hillel Grossman and Effie Mitsis and {de Toledo-Morrell}, Leyla and Shah, {Raj C.} and Ranjan Duara and Daniel Varon and Greig, {Maria T.} and Peggy Roberts and Chiadi Onyike and Daniel D{\textquoteright}Agostino and Stephanie Kielb and Galvin, {James E.} and Brittany Cerbone and Michel, {Christina A.} and Henry Rusinek and {de Leon}, {Mony J.} and Lidia Glodzik and {De Santi}, Susan and Doraiswamy, {P. Murali} and Petrella, {Jeffrey R.} and Wong, {Terence Z.} and Arnold, {Steven E.} and Karlawish, {Jason H.} and David Wolk and Smith, {Charles D.} and Greg Jicha and Peter Hardy and Partha Sinha and Elizabeth Oates and Gary Conrad and Lopez, {Oscar L.} and Oakley, {Mary Ann} and Simpson, {Donna M.} and Porsteinsson, {Anton P.} and Goldstein, {Bonnie S.} and Kim Martin and Makino, {Kelly M.} and Ismail, {M. Saleem} and Connie Brand and Mulnard, {Ruth A.} and Gaby Thai and Catherine McAdams-Ortiz and Kyle Womack and Kyle Womack and Mary Quiceno and Ramon Diaz-Arrastia and Richard King and Myron Weiner and Kristen Martin-Cook and Michael DeVous and Levey, {Allan I.} and Lah, {James J.} and Cellar, {Janet S.} and Burns, {Jeffrey M.} and Anderson, {Heather S.} and Swerdlow, {Russell H.} and Liana Apostolova and Kathleen Tingus and Ellen Woo and Silverman, {Daniel H.S.} and Lu, {Po H.} and George Bartzokis and Graff-Radford, {Neill R.} and Francine Parfitt and Tracy Kendall and Heather Johnson and Farlow, {Martin R.} and Hake, {Ann Marie} and Matthews, {Brandy R.} and Scott Herring and Cynthia Hunt and {van Dyck}, {Christopher H.} and Carson, {Richard E.} and MacAvoy, {Martha G.} and Howard Chertkow and Howard Bergman and Chris Hosein and Hsiung, {Ging Yuek Robin}",
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",
number = "7",
}