Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region

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 th...

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Bibliographic Details
Published in:Nature communications Vol. 12; no. 1; pp. 6115 - 12
Main Authors: Aneas, Ivy, Decker, Donna C., Howard, Chanie L., Sobreira, Débora R., Sakabe, Noboru J., Blaine, Kelly M., Stein, Michelle M., Hrusch, Cara L., Montefiori, Lindsey E., Tena, Juan, Magnaye, Kevin M., Clay, Selene M., Gern, James E., Jackson, Daniel J., Altman, Matthew C., Naureckas, Edward T., Hogarth, Douglas K., White, Steven R., Gomez-Skarmeta, Jose Luis, Schoetler, Nathan, Ober, Carole, Sperling, Anne I., Nóbrega, Marcelo A.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 21.10.2021
Nature Publishing Group
Nature Portfolio
Subjects:
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96/35
Alleles
Animals
Asthma
Asthma - genetics
Asthma - metabolism
Blood plasma
Chromatin
Chromatin - genetics
Chromatin - metabolism
Enhancer Elements, Genetic
Epithelial cells
Epithelium
Female
Gene expression
Genetic diversity
Genetic Predisposition to Disease
Genetic variance
Genome-wide association studies
Health risks
Humanities and Social Sciences
Humans
Interleukin-33 - genetics
Interleukin-33 - metabolism
Loci
Male
Mice, Transgenic
multidisciplinary
Nucleotides
Oct-1 protein
Octamer Transcription Factor-1 - genetics
Octamer Transcription Factor-1 - metabolism
Polymorphism
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Science
Science (multidisciplinary)
Signs and symptoms
Single-nucleotide polymorphism
Zebrafish
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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. Susceptibility to asthma and severity of symptoms are regulated by a number of different genomic regions. Here the authors characterise a 5kb regulatory region and demonstrate genetic and topological regulation of IL33 and association with disease in different human cohorts.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-26347-z