Portelli, M. A. et al. (2020) Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium. JCI Insight, 5(8), e132446. (doi: 10.1172/jci.insight.132446) (PMID:32324168) (PMCID:PMC7205441)
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Abstract
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.
Item Type: | Articles |
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Keywords: | Asthma, Cell Biology, Genetic variation, Genetics, Molecular genetics. |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Thomson, Professor Neil |
Authors: | Portelli, M. A., Dijk, F. N., Ketelaar, M. E., Shrine, N., Hankinson, J., Bhaker, S., Grotenboer, N. S., Obeidat, M.'e., Henry, A. P., Billington, C. K., Shaw, D., Johnson, S. R., Pogson, Z. E., Fogarty, A., McKeever, T. M., Nickle, D. C., Bossé, Y., van den Berge, M., Faiz, A., Brouwer, S., Vonk, J. M., de Vos, P., Brandsma, C.-A., Vermeulen, C. J., Singapuri, A., Heaney, L. G., Mansur, A. H., Chaudhuri, R., Thomson, N. C., Holloway, J. W., Lockett, G. A., Howarth, P. H., Niven, R., Simpson, A., Blakey, J. D., Tobin, M. D., Postma, D. S., Hall, I. P., Wain, L. V., Nawijn, M. C., Brightling, C. E., Koppelman, G. H., and Sayers, I. |
College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
Journal Name: | JCI Insight |
Publisher: | American Society for Clinical Investigation |
ISSN: | 2379-3708 |
ISSN (Online): | 2379-3708 |
Copyright Holders: | Copyright © 2020, Portelli et al. |
First Published: | First published in ICI insights 5(8):e132446 |
Publisher Policy: | Reproduced under a Creative Commons Licence |
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