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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 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.

2379-3708
1-19
Portelli, Michael A.
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Dijk, F. Nicole
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Ketelaar, Maria E
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Shrine, Nick
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Hankinson, Jenny
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Henry, Amanda P.
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Billington, Charlotte K.
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Johnson, Simon R
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McKeever, Tricia M.
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Nickle, David C
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Bossé, Yohan
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Van Den Berge, Maarten
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Vermeulen, Corneel
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Singapuri, Amisha
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Heaney, Liam G.
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Mansur, Adel H.
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Chaudhuri, Rekha
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Thomson, Neil C.
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Holloway, John
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Lockett, Gabrielle A
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Howarth, Peter
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Niven, Robert
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Simpson, Angela
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Blakey, John D
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Tobin, Martin D
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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.
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Dijk, F. Nicole
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Ketelaar, Maria E
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Shrine, Nick
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Hankinson, Jenny
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Bhaker, Sangita
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Grotenboer, Neomi S
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Obeidat, Ma'en
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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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Johnson, Simon R
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Pogson, Zara E.K.
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Fogarty, Andrew
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McKeever, Tricia M.
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Van Den Berge, Maarten
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Faiz, Alen
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Vonk, Judith M.
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de Vos, Paul
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Brandsma, Corry-Anke
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Vermeulen, Corneel
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Singapuri, Amisha
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Heaney, Liam G.
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Mansur, Adel H.
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Chaudhuri, Rekha
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Thomson, Neil C.
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Holloway, John
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Lockett, Gabrielle A
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Howarth, Peter
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Niven, Robert
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Simpson, Angela
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Blakey, John D
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Tobin, Martin D
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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 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.

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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
Additional Information: Funding Information: This study was funded by an Asthma UK Grant to IS, IPH, DES, and CEB (AUK-PG-2013-188) and additional Asthma UK funding to IS and DES (grants 10/006 and 11/031). Genotyping in GASP was additionally supported by Rosetrees Trust (grant to IS) and AirPROM (CEB, MT, and IS). This work was supported by the Medical Research Council (grant number MC_PC_12010), a Strategic Award to IPH, MDT, LVW, and Professor David Strachan. LVW holds a GSK/British Lung Foundation Chair in Respiratory Research. Asthma UK funded the GASP initiative (AUK-PG-2013-188). This work was part funded by the NIHR Leicester Respiratory Biomedical Centre. AS is supported by the NIHR Manchester Biomedical Research Centre. MAAS was supported by the Asthma UK grants (no. 301, 1995–1998; no. 362, 1998–2001; no. 01/012, 2001–2004; no. 04/014, 2004–2007; BMA James Trust, 2005; The JP Moul-ton Charitable Foundation, 2004–current; The North west Lung Centre Charity, 1997-current; the Medical Research Council (MRC) G0601361, 2007–2012; MR/K002449/1, 2013–2014; and MR/L012693/1, 2014–2018). The Lifelines Biobank initiative has been made possible by subsidy from the Dutch Ministry of Health, Welfare and Sport, the Dutch Ministry of Economic Affairs, UMCG (the Netherlands), University Groningen, and the Northern Provinces of the Netherlands. This study was also supported by a Lung Foundation of the Netherlands Dutch Lung Foundation (grant nos. AF 95.05, AF 98.48, and AF3.2.09. 081JU), the UMCG, Dutch TerMeulen Fund, and the Ubbo Emmius Fund (University of Groningen). The authors would like to thank Carl Nelson of Nottingham Trent University for his kind donation of HEK–NF-κB–SEAP reporter cells. The authors also wish to acknowledge the services of the Lifelines Cohort Study, the contributing research centers delivering data to Lifelines, and all the study participants. Publisher Copyright: © 2020, Portelli et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

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

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Date deposited: 26 Mar 2020 17:30
Last modified: 17 Mar 2024 05:25

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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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