IL1RL1 asthma risk variants regulate airway type 2 inflammation
Erin D. Gordon, … , John V. Fahy, Max A. Seibold
Erin D. Gordon, … , John V. Fahy, Max A. Seibold
Published September 8, 2016
Citation Information: JCI Insight. 2016;1(14):e87871. https://doi.org/10.1172/jci.insight.87871.
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Research Article Immunology Pulmonology

IL1RL1 asthma risk variants regulate airway type 2 inflammation

Abstract

Genome-wide association studies of asthma have identified genetic variants in the IL1RL1 gene, but the molecular mechanisms conferring risk are unknown. IL1RL1 encodes the ST2 receptor (ST2L) for IL-33 and an inhibitory decoy receptor (sST2). IL-33 promotes type 2 inflammation, which is present in some but not all asthmatics. We find that two single nucleotide polymorphisms (SNPs) in IL1RL1 — rs1420101 and rs11685480 — are strongly associated with plasma sST2 levels, though neither is an expression quantitative trait locus (eQTL) in whole blood. Rather, rs1420101 and rs11685480 mark eQTLs in airway epithelial cells and distal lung parenchyma, respectively. We find that the genetically determined plasma sST2 reservoir, derived from the lung, neutralizes IL-33 activity, and these eQTL SNPs additively increase the risk of airway type 2 inflammation among asthmatics. These risk variants define a population of asthmatics at risk of IL-33–driven type 2 inflammation.

Authors

Erin D. Gordon, Joe Palandra, Agata Wesolowska-Andersen, Lando Ringel, Cydney L. Rios, Marrah E. Lachowicz-Scroggins, Louis Z. Sharp, Jamie L. Everman, Hannah J. MacLeod, Jae W. Lee, Robert J. Mason, Michael A. Matthay, Richard T. Sheldon, Michael C. Peters, Karl H. Nocka, John V. Fahy, Max A. Seibold

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Figure 1

Biospecimens used to examine genetic regulation of the IL1RL1 locus.

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Biospecimens used to examine genetic regulation of the IL1RL1 locus. We ...
We explored protein and RNA expression genetics in both blood and lung tissue. We employed a clinical cohort of asthmatic and healthy control subjects, recruited at UCSF, to examine plasma protein sST2 levels using liquid chromatography mass-spectroscopy (LC-MS) and whole blood sST2 gene expression. We used a bank of cultured airway epithelial cells (both unstimulated [CTL] and stimulated with L-13) and an NIH-sponsored distal lung organ tissue gene expression repository (Genotype and Tissue Expression Project [GTEx], Broad Institute) to determine sST2 expression genetics in 2 lung tissue types: airway epithelium and distal lung tissue, respectively. Finally, we used a cohort of asthmatic subjects (UCSF) with airway measures of type 2 inflammation (i.e., endotyping) either by bronchial brush gene expression signatures or sputum cell cytokine expression profiles, to examine IL1RL1 genetic influence on asthma endotype.