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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, N�omi S.; Obeidat, Ma�en; Henry, Amanda P.; Billington, Charlotte K.; Shaw, Dominick; Johnson, Simon R.; Pogson, Zara E.K.; Fogarty, Andrew; McKeever, Tricia M.; Nickle, David C.; Boss�, 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 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.; Sayers, Ian

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


Authors

F. Nicole Dijk

Maria E. Ketelaar

Nick Shrine

Jenny Hankinson

Sangita Bhaker

N�omi S. Grotenboer

Ma�en Obeidat

Amanda P. Henry

Charlotte K. Billington

Dominick Shaw

SIMON JOHNSON simon.johnson@nottingham.ac.uk
Professor of Respiratory Medicine

Zara E.K. Pogson

ANDREW FOGARTY ANDREW.FOGARTY@NOTTINGHAM.AC.UK
Clinical Associate Professor & Reader in Clinical Epidemiology

TRICIA MCKEEVER tricia.mckeever@nottingham.ac.uk
Professor of Epidemiology and Medical Statistics

David C. Nickle

Yohan Boss�

Maarten van den Berge

Alen Faiz

Sharon Brouwer

Judith M. Vonk

Paul de Vos

Corry Anke Brandsma

Corneel 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 HALL IAN.HALL@NOTTINGHAM.AC.UK
Professor of Molecular Medicine

Louise V. Wain

Martijn C. Nawijn

Christopher E. Brightling

Gerard H. Koppelman



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-?B 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.

Citation

Portelli, M. A., Dijk, F. N., Ketelaar, M. E., Shrine, N., Hankinson, J., Bhaker, S., …Sayers, I. (2020). Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium. JCI insight, 5(8), Article 132446. https://doi.org/10.1172/jci.insight.132446

Journal Article Type Article
Acceptance Date Mar 12, 2020
Online Publication Date Apr 23, 2020
Publication Date Apr 23, 2020
Deposit Date Apr 3, 2020
Publicly Available Date Mar 28, 2024
Journal JCI insight
Electronic ISSN 2379-3708
Peer Reviewed Peer Reviewed
Volume 5
Issue 8
Article Number 132446
DOI https://doi.org/10.1172/jci.insight.132446
Public URL https://nottingham-repository.worktribe.com/output/4246845
Publisher URL https://insight.jci.org/articles/view/132446

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