Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region
Ivy Aneas, Donna C. Decker, Chanie L. Howard, Débora R. Sobreira, Noboru J. Sakabe, Kelly Blaine, Michelle M. Stein, Cara L. Hrusch, Lindsey E. Montefiori, Juan J. Tena, Kevin M. Magnaye, Selene M. Clay, James E. Gern, Daniel J. Jackson, Matthew C. Altman, Edward T. Naureckas, D. Kyle Hogarth, Steven R. White, José Luis Gómez-Skármeta, Nathan Schoetler, Carole Ober, Anne I. Sperling, Marcelo A. Nóbrega
Abstract
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 an enhancer-blocking 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 the asthma-associated single nucleotide polymorphism (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 mechanism through which a regulatory SNP contributes to genetic risk of asthma.