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 2

Single nucleotide polymorphisms (SNPs) in the IL1RL1 gene influence plasma protein sST2 levels but not whole blood cell sST2 expression.

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Single nucleotide polymorphisms (SNPs) in the IL1RL1 gene influence plas...
(A) Schematic showing the IL1RL1 gene transcript structure highlighting 5 candidate expression quantitative trait loci (eQTL) SNPs. Blue exons are specific to the ST2L transcript, green exons are specific to the sST2 transcript, and red exons are shared by both transcripts. The distal promoter can produce both the long ST2L and the short sST2 transcript, while the proximal can produce only the short sST2 transcript. (B) sST2 plasma protein levels (red) as measured by liquid chromatography-mass spectroscopy (LC-MS) are associated with 3 SNPs in the IL1RL1 gene: rs11685480, rs1420101, and rs1921622 in white non-Hispanic subjects only (WNH) and among the entire cohort (All). The tested allele in all cases is associated with lower-circulating sST2 levels. None of the tested SNPs was an eQTL for sST2 expression in whole blood RNA (blue). SNP regression coefficient and the corresponding 95% CIs are plotted with P values listed below. Additive linear regression models were used. Nonitalicized P values indicate the WNH, while the italicized P values shown for the entire cohort (All).