An Allergy-Associated Polymorphism in a Novel Regulatory Element Enhances IL13 Expression (136.27)

Abstract

Abstract The cytokine IL13 is a critical effector of T helper 2 (Th2)-mediated responses and allergic inflammation. We previously characterized the function of common IL13 variants that show strong, replicated associations with allergy-related phenotypes. We also demonstrated that during CD4+ Th cell differentiation, chromatin at the IL13 locus is extensively remodeled and becomes hypersensitive to nucleases at multiple sites. Among these, HS4 in the distal promoter is constitutively present in naïve and differentiated T cells, and spans a common allergy-associated SNP, IL13-1512AC (rs1881457). Here we characterize HS4 as a novel cis-regulatory element that upregulates IL13 transcription in Th2 cells and we show that the rs1881457 risk allele significantly alters HS4 activity and enhances IL13 promoter activity by creating a binding site for the transcription factor Oct-1. Experiments in mice heterozygous for an Oct-1 null mutation demonstrated that physiologic levels of Oct-1 are required for increased expression of the IL13-1512C promoter allele. Our results illustrate how a functional variant in a regulatory element may modulate susceptibility to a common complex disease.