title: IL1RL1asthma risk variants regulate airway type 2 inflammation.
abstract: Genome-wide association studies of asthma have identified genetic variants in theIL1RL1gene, but the molecular mechanisms conferring risk are unknown.IL1RL1encodes 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) inIL1RL1- 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.affiliation: Department of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Erin D
authors.initials: ED
authors.lastname: Gordon
authors.affiliation: Pfizer Inc., Pharmacodynamics and Metabolism, Andover, Massachusetts, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Palandra
authors.affiliation: Center for Genes, Environment, and Health, National Jewish Health, Denver, Colorado, USA.
authors.forename: Agata
authors.initials: A
authors.lastname: Wesolowska-Andersen
authors.affiliation: Center for Genes, Environment, and Health, National Jewish Health, Denver, Colorado, USA.
authors.forename: Lando
authors.initials: L
authors.lastname: Ringel
authors.affiliation: Center for Genes, Environment, and Health, National Jewish Health, Denver, Colorado, USA.
authors.forename: Cydney L
authors.initials: CL
authors.lastname: Rios
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Marrah E
authors.initials: ME
authors.lastname: Lachowicz-Scroggins
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Louis Z
authors.initials: LZ
authors.lastname: Sharp
authors.affiliation: Center for Genes, Environment, and Health, National Jewish Health, Denver, Colorado, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Everman
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: MacLeod
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.|Department of Anesthesiology, UCSF, San Francisco, California, USA.
authors.forename: Jae W
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Medicine, National Jewish Health, Denver, Colorado, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mason
authors.affiliation: Department of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, California, USA.|Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.|Department of Anesthesiology, UCSF, San Francisco, California, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.affiliation: Pfizer Inc., Inflammation and Immunology, Cambridge, Massachusetts, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Sheldon
authors.affiliation: Department of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Peters
authors.affiliation: Pfizer Inc., Inflammation and Immunology, Cambridge, Massachusetts, USA.
authors.forename: Karl H
authors.initials: KH
authors.lastname: Nocka
authors.affiliation: Department of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, California, USA.|Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.
authors.forename: John V
authors.initials: JV
authors.lastname: Fahy
authors.affiliation: Center for Genes, Environment, and Health, National Jewish Health, Denver, Colorado, USA.|Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.|Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado-Denver, Denver, Colorado, USA.
authors.forename: Max A
authors.initials: MA
authors.lastname: Seibold
mesh_terms: D001249:Asthma / Q000235:genetics*; D002478:Cells, Cultured; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000235:genetics*; D000067596:Interleukin-33; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33