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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Cold Spring Harbor
Cold Spring Harbor Laboratory Press
11.09.2020
Cold Spring Harbor Laboratory |
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| Abstract | 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. |
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| AbstractList | 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. 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. |
| Author | Montefiori, Lindsey E White, Steven R Sperling, Anne I Tena, Juan Gomez-Skarmeta, Jose Luis Gern, James E Naureckas, Edward T Ober, Carole Nobrega, Marcelo A Stein, Michelle M Clay, Selene M Jackson, Daniel J Hogarth, Douglas K Hrusch, Cara L Decker, Donna C Sobreira, Débora R Schoetler, Nathan Blaine, Kelly M Howard, Chanie L Altman, Matthew C Aneas, Ivy Sakabe, Noboru J Magnaye, Kevin M |
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| Snippet | ABSTRACT Genome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5... 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... |
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| SubjectTerms | Alleles Asthma Chromatin Epithelial cells Gene expression Genome-wide association studies Genomes Genomics Genotypes Oct-1 protein Single-nucleotide polymorphism |
| Title | Asthma-associated variants induce IL33 differential expression through a novel regulatory region |
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