@article{10.1172/jci.insight.87871, author = {Erin D. Gordon AND Joe Palandra AND Agata Wesolowska-Andersen AND Lando Ringel AND Cydney L. Rios AND Marrah E. Lachowicz-Scroggins AND Louis Z. Sharp AND Jamie L. Everman AND Hannah J. MacLeod AND Jae W. Lee AND Robert J. Mason AND Michael A. Matthay AND Richard T. Sheldon AND Michael C. Peters AND Karl H. Nocka AND John V. Fahy AND Max A. Seibold}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {IL1RL1 asthma risk variants regulate airway type 2 inflammation}, year = {2016}, month = {9}, volume = {1}, url = {https://insight.jci.org/articles/view/87871}, 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.}, number = {14}, doi = {10.1172/jci.insight.87871}, url = {https://doi.org/10.1172/jci.insight.87871}, }