Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region.
Ivy AneasDonna C DeckerChanie L HowardDébora R SobreiraNoboru J SakabeKelly M BlaineMichelle M SteinCara L HruschLindsey E MontefioriJuan J TenaKevin M MagnayeSelene M ClayJames E GernDaniel J JacksonMatthew C AltmanEdward T NaureckasDouglas K HogarthSteven R WhiteJose Luis Gomez-SkarmetaNathan SchoetlerCarole OberAnne I SperlingMarcelo A NobrégaPublished in: Nature communications (2021)
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.
Keyphrases
- chronic obstructive pulmonary disease
- gene expression
- lung function
- transcription factor
- allergic rhinitis
- genome wide
- poor prognosis
- binding protein
- dna methylation
- endothelial cells
- electronic health record
- oxidative stress
- genome wide association
- long non coding rna
- high density
- artificial intelligence
- breast cancer risk