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

Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium
Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium
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 remains 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. Utilising four independent cohorts (Lifelines, DAG, GASP & MAAS) and resequencing data, we identified three 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 non-synonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all four signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signalling domain haplotype affected IL-33 driven NF-KB signalling, whilst not interfering with Toll-like receptor signalling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, and provide initial mechanistic insight including genetic regulation of IL1RL1 isoform expression and receptor signalling.
2379-3708
1-19
Portelli, Michael A.
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Dijk, F. Nicole
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Hankinson, Jenny
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Koppelman, Gerard H
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Portelli, Michael A.
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Ketelaar, Maria E
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Hankinson, Jenny
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Grotenboer, Neomi S
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Henry, Amanda P.
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Billington, Charlotte K.
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Shaw, Dominick E.
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Chaudhuri, Rekha
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Thomson, Neil C.
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Holloway, John
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Postma, Dirkje S.
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Hall, Ian P.
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Wain, Louise V.
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Nawijn, Martijn C.
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Brightling, Christopher E.
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Koppelman, Gerard H
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Sayers, Ian
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Portelli, Michael A., Dijk, F. Nicole, Ketelaar, Maria E, Shrine, Nick, Hankinson, Jenny, Bhaker, Sangita, Grotenboer, Neomi S, Obeidat, Ma'en, Henry, Amanda P., Billington, Charlotte K., Shaw, Dominick E., Johnson, Simon R, Pogson, Zara E.K., 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, Corneel, Singapuri, Amisha, Heaney, Liam G., Mansur, Adel H., Chaudhuri, Rekha, Thomson, Neil C., Holloway, John, Lockett, Gabrielle A, Howarth, Peter, 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), 1-19, [e132446]. (doi:10.1172/jci.insight.132446).

Record type: Article

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 remains 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. Utilising four independent cohorts (Lifelines, DAG, GASP & MAAS) and resequencing data, we identified three 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 non-synonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all four signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signalling domain haplotype affected IL-33 driven NF-KB signalling, whilst not interfering with Toll-like receptor signalling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, and provide initial mechanistic insight including genetic regulation of IL1RL1 isoform expression and receptor signalling.

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Accepted/In Press date: 13 March 2020
e-pub ahead of print date: 23 April 2020
Published date: 23 April 2020

Identifiers

Local EPrints ID: 438875
URI: http://eprints.soton.ac.uk/id/eprint/438875
ISSN: 2379-3708
PURE UUID: 11bb3d78-45b1-4617-b408-c591650f4cb0
ORCID for John Holloway: ORCID iD orcid.org/0000-0001-9998-0464

Catalogue record

Date deposited: 26 Mar 2020 17:30
Last modified: 26 Nov 2021 05:56

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Contributors

Author: Michael A. Portelli
Author: F. Nicole Dijk
Author: Maria E Ketelaar
Author: Nick Shrine
Author: Jenny Hankinson
Author: Sangita Bhaker
Author: Neomi S Grotenboer
Author: Ma'en Obeidat
Author: Amanda P. Henry
Author: Charlotte K. Billington
Author: Dominick E. Shaw
Author: Simon R Johnson
Author: Zara E.K. Pogson
Author: Andrew Fogarty
Author: Tricia M. McKeever
Author: David C Nickle
Author: Yohan Bossé
Author: Maarten Van Den Berge
Author: Alen Faiz
Author: Sharon Brouwer
Author: Judith M. Vonk
Author: Paul de Vos
Author: Corry-Anke Brandsma
Author: Corneel Vermeulen
Author: Amisha Singapuri
Author: Liam G. Heaney
Author: Adel H. Mansur
Author: Rekha Chaudhuri
Author: Neil C. Thomson
Author: John Holloway ORCID iD
Author: Gabrielle A Lockett
Author: Peter Howarth
Author: Robert Niven
Author: Angela Simpson
Author: John D Blakey
Author: Martin D Tobin
Author: Dirkje S. Postma
Author: Ian P. Hall
Author: Louise V. Wain
Author: Martijn C. Nawijn
Author: Christopher E. Brightling
Author: Gerard H Koppelman
Author: Ian Sayers

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