title: Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling.
abstract: The suppression of tumorigenicity 2/IL-33 (ST2/IL-33) pathway has been implicated in several immune and inflammatory diseases. ST2 is produced as 2 isoforms. The membrane-bound isoform (ST2L) induces an immune response when bound to its ligand, IL-33. The other isoform is a soluble protein (sST2) that is thought to be a decoy receptor for IL-33 signaling. Elevated sST2 levels in serum are associated with an increased risk for cardiovascular disease. We investigated the determinants of sST2 plasma concentrations in 2,991 Framingham Offspring Cohort participants. While clinical and environmental factors explained some variation in sST2 levels, much of the variation in sST2 production was driven by genetic factors. In a genome-wide association study (GWAS), multiple SNPs within IL1RL1 (the gene encoding ST2) demonstrated associations with sST2 concentrations. Five missense variants of IL1RL1 correlated with higher sST2 levels in the GWAS and mapped to the intracellular domain of ST2, which is absent in sST2. In a cell culture model, IL1RL1 missense variants increased sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness (via ST2L). Our data suggest that genetic variation in IL1RL1 can result in increased levels of sST2 and alter immune and inflammatory signaling through the ST2/IL-33 pathway.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Ho
authors.forename: Wei-Yu
authors.initials: WY
authors.lastname: Chen
authors.forename: Ming-Huei
authors.initials: MH
authors.lastname: Chen
authors.forename: Martin G
authors.initials: MG
authors.lastname: Larson
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: McCabe
authors.forename: Susan
authors.initials: S
authors.lastname: Cheng
authors.forename: Anahita
authors.initials: A
authors.lastname: Ghorbani
authors.forename: Erin
authors.initials: E
authors.lastname: Coglianese
authors.forename: Valur
authors.initials: V
authors.lastname: Emilsson
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Johnson
authors.forename: Stefan
authors.initials: S
authors.lastname: Walter
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
authors.forename: Chen
authors.initials: C
authors.lastname: Lu
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.forename: Honghuang
authors.initials: H
authors.lastname: Lin
authors.forename: Janine F
authors.initials: JF
authors.lastname: Felix
authors.forename: Eric R
authors.initials: ER
authors.lastname: Schreiter
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.forename: James L
authors.initials: JL
authors.lastname: Januzzi
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lee
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wang
mesh_terms: D019943:Amino Acid Substitution; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: C079241:IL1RL1 protein, human; C506536:IL33 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; C569026:MAL protein, human; C507779:MYD88 protein, human; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D018808:Transcription Factor AP-1