The IL1RL1 (ST2) gene locus is robustly associated with asthma; however, the contribution of single nucleotide polymorphisms (SNPs) in this locus to specific asthma subtypes and the functional mechanisms underlying these associations remain to be defined. We tested for association between IL1RL1 region SNPs and characteristics of asthma as defined by clinical and immunological measures and addressed functional effects of these genetic variants in lung tissue and airway epithelium. Utilizing 4 independent cohorts (Lifelines, Dutch Asthma GWAS [DAG], Genetics of Asthma Severity and Phenotypes [GASP], and Manchester Asthma and Allergy Study [MAAS]) and resequencing data, we identified 3 key signals associated with asthma features. Investigations in lung tissue and primary bronchial epithelial cells identified context-dependent relationships between the signals and IL1RL1 mRNA and soluble protein expression. This was also observed for asthma-associated IL1RL1 nonsynonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all 4 signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signaling domain haplotype affected IL-33-driven NF-κB signaling, while not interfering with TLR signaling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, as well as provide initial mechanistic insight, including genetic regulation of IL1RL1 isoform expression and receptor signaling.
About The Expert
Michael A Portelli
F Nicole Dijk
Maria E Ketelaar
Nick Shrine
Jenny Hankinson
Sangita Bhaker
Néomi S Grotenboer
Ma’en Obeidat
Amanda P Henry
Charlotte K Billington
Dominick Shaw
Simon R Johnson
Zara Ek Pogson
Andrew Fogarty
Tricia M McKeever
David C Nickle
Yohan Bossé
Maarten van den Berge
Alen Faiz
Sharon Brouwer
Judith M Vonk
Paul de Vos
Corry-Anke Brandsma
Cornelis J Vermeulen
Amisha Singapuri
Liam G Heaney
Adel H Mansur
Rekha Chaudhuri
Neil C Thomson
John W Holloway
Gabrielle A Lockett
Peter H Howarth
Robert Niven
Angela Simpson
John D Blakey
Martin D Tobin
Dirkje S Postma
Ian P Hall
Louise V Wain
Martijn C Nawijn
Christopher E Brightling
Gerard H Koppelman
Ian Sayers
References
PubMed