Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region

Nat Commun. 2021 Oct 21;12(1):6115. doi: 10.1038/s41467-021-26347-z.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Animals
  • Asthma / genetics*
  • Asthma / metabolism
  • Chromatin / genetics
  • Chromatin / metabolism
  • Enhancer Elements, Genetic*
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Interleukin-33 / genetics*
  • Interleukin-33 / metabolism
  • Male
  • Mice, Transgenic
  • Octamer Transcription Factor-1 / genetics
  • Octamer Transcription Factor-1 / metabolism
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Zebrafish


  • Chromatin
  • Interleukin-33
  • Octamer Transcription Factor-1