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Ho, J.E.* ; Chen, W.Y.* ; Chen, M.H.* ; Larson, M.G.* ; McCabe, E.L.* ; Cheng, S.* ; Ghorbani, A.* ; Coglianese, E.* ; Emilsson, V.* ; Johnson, A.D.* ; Walter, S.* ; Franceschini, N.* ; O'Donnell, C.J.* ; CARDIoGRAM Consortium (Wichmann, H.-E. ; Döring, A. ; Illig, T. ; Meisinger, C. ; Peters, A. ; Meitinger, T. ; Klopp, N.) ; CHARGE Inflammation Working Group (*) ; Dehghan, A.* ; Lu, C.* ; Levy, D.* ; Newton-Cheh, C.* ; CHARGE Consortium Heart Failure Group (*) ; Lin, H.* ; Felix, J.F.* ; Schreiter, E.R.* ; Vasan, R.S.* ; Januzzi, J.L. Jr.* ; Lee, R.T.* ; Wang, T.J.* ; Assimes, T.L.* ; Deloukas, P.* ; Erdmann, J.* ; Holm, H.* ; Kathiresan, S.* ; König, I.R.* ; McPherson, R.* ; Reilly, M.P.* ; Roberts, R.* ; Samani, N.J.* ; Schunkert, H.* ; Stewart, A.F.*

Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling.

J. Clin. Invest. 123, 4208-4218 (2013)
Publ. Version/Full Text Volltext DOI PMC
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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.
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Publication type Article: Journal article
Document type Scientific Article
Language english
Publication Year 2013
HGF-reported in Year 2013
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Journal Journal of Clinical Investigation
Quellenangaben Volume: 123, Issue: 10, Pages: 4208-4218 Article Number: , Supplement: ,
Publisher American Society of Clinical Investigation
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)
Research Unit Molecular Epidemiology (AME)
Institute of Human Genetics (IHG)
POF-Topic(s) 30202 - Environmental Health
30503 - Chronic Diseases of the Lung and Allergies
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-504000-006
G-503900-001
G-504200-001
G-504000-002
G-500700-001
PubMed ID 23999434
DOI 10.1172/JCI67119
Erfassungsdatum 2013-12-31
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