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JCI Insight. 2016 Sep 8;1(14):e87871. doi: 10.1172/jci.insight.87871.

IL1RL1 asthma risk variants regulate airway type 2 inflammation.

Author information

1
Department of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, California, USA.
2
Pfizer Inc., Pharmacodynamics and Metabolism, Andover, Massachusetts, USA.
3
Center for Genes, Environment, and Health, National Jewish Health, Denver, Colorado, USA.
4
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.
5
Department of Anesthesiology, UCSF, San Francisco, California, USA.
6
Department of Medicine, National Jewish Health, Denver, Colorado, USA.
7
Pfizer Inc., Inflammation and Immunology, Cambridge, Massachusetts, USA.
8
Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
9
Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado-Denver, Denver, Colorado, USA.

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.

PMID:
27699235
PMCID:
PMC5033813
DOI:
10.1172/jci.insight.87871
[Indexed for MEDLINE]
Free PMC Article

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