IL1RL1 asthma risk variants regulate airway type 2 inflammation
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
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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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 5

sST2 expression is increased in the airway in the subset of asthmatics with type 2 inflammation and is regulated by IL-13.

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sST2 expression is increased in the airway in the subset of asthmatics ...
(A) In bronchial brush RNA from asthmatics (n = 83) and healthy controls (n = 22), sST2 gene expression is increased only in the subset that demonstrates evidence of excessive type 2 airway inflammation (type 2-high). P value reflects ordinary 1-way ANOVA. In cultured human airway epithelial cells, we find that variance stabilizing transformation–normalized (VST-normalized) sST2 gene expression (n = 127) (B) and secreted protein (n = 141) (C) are strongly increased from baseline levels (CTL) following IL-13 stimulation. P values reflects 2-tailed paired t tests. Data presented as Tukey box plots with box containing the first and third quartile, line at median, and whiskers at 1.5 interquartile range.