Asthma-associated variants induce IL33 differential expression through a novel regulatory region
Aneas, I.; Decker, D. C.; Howard, C. L.; Sobreira, D. R.; Sakabe, N.; Blaine, K. M.; Stein, M. M.; Hrusch, C. L.; Montefiori, L. E.; Tena, J. J.; Magnaye, K. M.; Clay, S. M.; Gern, J. E.; Jackson, D. J.; Altman, M. C.; Naureckas, E. T.; Hogarth, D. K.; White, S. R.; Gomez-Skarmeta, J. L.; Schoetler, N.; Ober, C.; Sperling, A. I.; Nobrega, M. A.
Show 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 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. Supporting this notion, we show that genotype at an 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.
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