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

journal contribution
posted on 2020-06-09, 10:38 authored by Michael A Portelli, F Nicole Dijk, Maria E Ketelaar, Nick Shrine, Jenny Hankinson, Sangita Bhaker, Neomi S Grotenboer, Ma'en Obeidat, Amanda P Henry, Charlotte K Billington, Dominick Shaw, Simon R Johnson, Zara EK Pogson, Andrew Fogarty, Tricia M McKeever, David C Nickle, Yohan Bosse, Maarten van den Berge, Alen Faiz, Sharon Brouwer, Judith M Vonk, Paul de Vos, Corry-Anke Brandsma, Cornelis J 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 P Hall, Louise Wain, Martijn C Nawijn, Christopher E Brightling, Gerard H Koppelman, Ian Sayers
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.

Funding

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 Moulton 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.

History

Citation

JCI Insight. 2020;5(8):e132446. https://doi.org/10.1172/jci.insight.132446.

Version

  • VoR (Version of Record)

Published in

JCI INSIGHT

Volume

5

Issue

8

Pagination

e132446 (18)

Publisher

AMER SOC CLINICAL INVESTIGATION INC

issn

2379-3708

eissn

2379-3708

Acceptance date

2020-03-12

Copyright date

2020

Language

English

Publisher version

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