Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling
Jennifer E. Ho, … , Richard T. Lee, Thomas J. Wang
Jennifer E. Ho, … , Richard T. Lee, Thomas J. Wang
Published September 3, 2013
Citation Information: J Clin Invest. 2013;123(10):4208-4218. https://doi.org/10.1172/JCI67119.
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Research Article Immunology

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

Jennifer E. Ho, Wei-Yu Chen, Ming-Huei Chen, Martin G. Larson, Elizabeth L. McCabe, Susan Cheng, Anahita Ghorbani, Erin Coglianese, Valur Emilsson, Andrew D. Johnson, Stefan Walter, Nora Franceschini, Christopher J. O’Donnell, Abbas Dehghan, Chen Lu, Daniel Levy, Christopher Newton-Cheh, Honghuang Lin, Janine F. Felix, Eric R. Schreiter, Ramachandran S. Vasan, James L. Januzzi, Richard T. Lee, Thomas J. Wang

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Figure 2

Models of ST2 illustrate IL1RL1 missense variant locations.

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Models of ST2 illustrate IL1RL1 missense variant locations. Models of ...
Models of the (A) intracellular TIR domain (ST2-TIR) and the (B) extracellular domain (ST2-ECD) of ST2 (protein data bank codes 3O4O and 1T3G, respectively). Domains of ST2 are shown in yellow, with identified missense SNP positions represented as red spheres and labels. Note that positions 549 and 551 are near the C terminus of ST2, which is not defined in the crystal structure (protein data bank ID 1T3G, shown as dashed black line in A). Arrows point toward the transmembrane domain, which is also not observed in crystal structures.