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

Portelli, Michael A, Dijk, F Nicole, Ketelaar, Maria E, Shrine, Nick, Hankinson, Jenny, Bhaker, Sangita, Grotenboer, Néomi S, Obeidat, Ma'en, Henry, Amanda P, Billington, Charlotte K, Shaw, Dominick, Johnson, Simon R, Pogson, Zara Ek, Fogarty, Andrew, McKeever, Tricia M, Nickle, David C, Bossé, Yohan, van den Berge, Maarten, Faiz, Alen, Brouwer, Sharon, Vonk, Judith M, de Vos, Paul, Brandsma, Corry-Anke, Vermeulen, Cornelis J, Singapuri, Amisha, Heaney, Liam G, Mansur, Adel H, Chaudhuri, Rekha, Thomson, Neil C, Holloway, John W, Lockett, Gabrielle A, Howarth, Peter H, Niven, Robert, Simpson, Angela, Blakey, John D, Tobin, Martin D, Postma, Dirkje S, Hall, Ian P, Wain, Louise V, Nawijn, Martijn C, Brightling, Christopher E, Koppelman, Gerard H and Sayers, Ian (2020) Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium. JCI insight, 5 (8). ISSN 2379-3708. This article is available to all UHB staff and students via ASK Discovery tool

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Official URL: https://insight.jci.org/articles/view/132446

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: Article
Additional Information: This article is available to all UHB staff and students via ASK Discovery tool
Subjects: WF Respiratory system. Respiratory medicine
Divisions: Planned IP Care > Respiratory Medicine
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Depositing User: Beth Connors
Date Deposited: 11 May 2020 12:55
Last Modified: 11 May 2020 12:55
URI: http://www.repository.uhblibrary.co.uk/id/eprint/3036

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