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 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.
Highlights
Genome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear
We described an integrated pipeline to fine-map and functionally annotate the asthma-associated locus that includes the IL33 gene
Epigenetic signatures further reduced this region to 5 kb, which we demonstrated to have a crucial function in the development of chromatin loops creating contacts between IL33 promoters and regulatory elements within the critical interval to control IL33 expression
Summary
Genome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Genetic factors account for more than half of the overall disease liability[1] and genome-wide association studies (GWAS) have discovered more than 60 loci contributing to asthma disease risk[2], with most of the associated variants located in noncoding regions. Linking these noncoding variants to genes and understanding the mechanisms through which they impart disease risk remains an outstanding task for most asthma GWAS loci. The single-nucleotide polymorphisms (SNPs) associated with increased asthma risk at the IL33 GWAS locus reside within a linkage disequilibrium (LD) block in a noncoding genomic segment located 2.3 kb upstream of the IL33 gene. Our study provides functional insights into the function of common regulatory variants at the IL33 locus and illustrates how a causal SNP can exert phenotypic effects by modulating the function of regulatory elements that do not fit into standard definitions of enhancers, insulators, or repressors
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