Phenotypic and functional translation of IL33 genetics in asthma

Ketelaar, Maria E.; Portelli, Michael A.; Dijk, F. Nicole; Shrine, Nick; Faiz, Alen; Vermeulen, Cornelis J.; Xu, Cheng J.; Hankinson, Jenny; Bhaker, Sangita; Henry, Amanda P.; Billington, Charlote K.; Shaw, Dominick E.; Johnson, Simon R.; Benest, Andrew; Pang, Vincent; Bates, David O.; Pogson, Zara E.K.; Fogarty, Andrew; McKeever, Tricia M.; 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; Tobin, Martin D.; Hall, Ian P.; Wain, Louise V.; Blakey, John D.; Brightling, Christopher E.; Obeidat, Ma'en; Sin, Don D.; Nickle, David C.; Boss�, Yohan; Vonk, Judith M.; van den Berge, Maarten; Koppelman, Gerard H.; Sayers, Ian; Nawijn, Martijn C.

Abstract

© 2020 Background: Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown. Objective: This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function. Methods: Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs. Results: We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV1, FEV1/forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species–capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function. Conclusions: We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.

Citation

Ketelaar, M. E., Portelli, M. A., Dijk, F. N., Shrine, N., Faiz, A., Vermeulen, C. J., …Nawijn, M. C. (2021). Phenotypic and functional translation of IL33 genetics in asthma. Journal of Allergy and Clinical Immunology, 147(1), 144-157. https://doi.org/10.1016/j.jaci.2020.04.051

• Journal Article Type: Article
• Acceptance Date: Apr 14, 2020
• Online Publication Date: May 19, 2020
• Publication Date: 2021-01
• Deposit Date: Apr 24, 2020
• Publicly Available Date: May 20, 2021
• Journal: Journal of Allergy and Clinical Immunology
• Print ISSN: 0091-6749
• Electronic ISSN: 1097-6825
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 147
• Issue: 1
• Pages: 144-157
• DOI: https://doi.org/10.1016/j.jaci.2020.04.051
• Keywords: Immunology; Immunology and Allergy
• Public URL: https://nottingham-repository.worktribe.com/output/4332718
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0091674920306801
• Additional Information: Additional sources of funding:; Innovative Medicines Initiative joint undertaking under grant agreement 115010, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations companies' in-kind contributions (www.imi.europa.eu).; NIHR Nottingham Biomedical Research Centre; Manchester Biomedical Research Centre; Medical Research Council Clinical Research Training Fellowship; GSK/ British Lung Foundation