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Asthma-associated variants induce IL33 differential expression through a novel regulatory region

Ivy Aneas1, Donna C. Decker2, Débora R. Sobreira1, Noboru J. Sakabe1, Kelly M. Blaine2, Kevin M. Magnaye1, Selene M. Clay1, Carole Ober1, Anne I. Sperling2,3, Marcelo A. Nobrega1.

1- Department of Human Genetics, University of Chicago, Chicago, IL; 2- Department of Medicine, Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, 3- Committee on Immunology, University of Chicago, Chicago IL

Genome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5 kb region within the GWAS-defined segment that acts as a strong regulatory element in vivo and in vitro. Chromatin conformation capture showed that this 5 kb region loops to the IL33 promoter, potentially regulating its expression. We show that genotype at the asthma-associated SNP rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein expression in human plasma, potentially through differential binding of OCT-1 (POU2F1) to the asthma-risk allele. Our data demonstrate that asthma-associated variants at the IL33 locus mediate allele-specific regulatory activity and IL33 expression, providing a novel mechanism through which a regulatory SNP contributes to genetic risk of asthma.