Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and airway epithelium in asthma

Background The IL1RL1 (ST2) gene locus has been reproducibly associated with asthma. However, the contribution of this locus to specific asthma-subtypes remains undefined. Therefore, we tested association of IL1RL1 region SNPs to subtypes of asthma as defined by clinical and immunological measures and addressed their functional effects in lung tissue and airway epithelium. Methods and results Utilising three independent cohorts and resequencing data, we identified six key IL1RL1 locus signals that drive association with multiple asthma-subtypes, with the most significant signals being associated with blood eosinophil counts, atopy and childhood-onset asthma. Investigations in lung tissue and primary bronchial epithelial cell cultures identified context-dependent relationships between the six key SNPs and expression of different IL1RL1 mRNA isoforms and soluble ST2 protein. Asthma bronchial epithelial cell cultures exposed to exacerbation-relevant stimulations (IL33, Rhinovirus 16 and House Dust Mite) revealed modulatory effects for three SNPs (rs13431828, rs1420101 and rs12465392) towards IL1RL1 mRNA and protein expression suggesting SNP-environment interactions. A four amino acid changing haplotype in the IL1RL1 TIR domain tagged by rs10192157, affected IL33 driven NF-Kβ signalling, whilst not interfering with Toll-like receptor signalling. Conclusion In summary, multiple independent mechanisms regulated by different SNPs may explain the complexity of the IL1RL1 region as an association signal in asthma GWAS. 63 Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and airway epithelium in asthma