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 6

IL1RL1 eQTL single nucleotide polymorphisms (SNPs) are associated with risk of type 2 airway inflammation.

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IL1RL1 eQTL single nucleotide polymorphisms (SNPs) are associated with ...
(A) Both eQTL SNPs rs1420101 and rs11685480 are associated with risk of type 2 airway inflammation in asthma. Alleles associated with lower plasma sST2 and lower lung sST2 expression are also associated with increased risk of type 2-high asthma endotype. SNP odds ratios (OR) represent results of logistic regression analysis. (B) The increasing number of risk alleles for rs1420101 and rs11685480 demonstrates a step-wise decrease in circulating sST2 plasma levels (red, white non-Hispanic; blue, entire cohort [All]). P values from parametric ANOVA trend test across increasing number of risk alleles. Data presented as Tukey box plots with box containing the first and third quartile, line at median, and whiskers at 1.5 interquartile range. (C) The presence of 3–4 rs1420101/rs11685480 risk alleles is associated with increased risk of type 2 airway inflammation in asthma compared with the presence of 0–2 risk alleles, with an OR of 2.85, which is greater than either risk genotype alone.