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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Podrobná bibliografia
Vydané v:	bioRxiv
Hlavní autori:	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
Médium:	Paper
Jazyk:	English
Vydavateľské údaje:	Cold Spring Harbor Cold Spring Harbor Laboratory Press 11.09.2020 Cold Spring Harbor Laboratory
Vydanie:	1.1
Predmet:	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
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Popis
Shrnutí:	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.
Bibliografia:	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