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

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...

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Published in:bioRxiv
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, Nobrega, Marcelo A
Format: Paper
Language:English
Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 11.09.2020
Cold Spring Harbor Laboratory
Edition:1.1
Subjects:
Alleles
Asthma
Chromatin
Epithelial cells
Gene expression
Genome-wide association studies
Genomes
Genomics
Genotypes
Oct-1 protein
Single-nucleotide polymorphism
ISSN:2692-8205, 2692-8205
Online Access:Get full text
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Summary: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. Competing Interest Statement The authors have declared no competing interest.
Bibliography:SourceType-Working Papers-1
ObjectType-Working Paper/Pre-Print-1
content type line 50
Competing Interest Statement: The authors have declared no competing interest.
ISSN:2692-8205
2692-8205
DOI:10.1101/2020.09.09.290098