Phenotypic and functional translation of IL33 genetics in asthma.

Ketelaar, Maria E, Portelli, Michael A, Dijk, F Nicole, Shrine, N, Faiz, A, Vermeulen, C J, Xu, C J, Hankinson, J, Bhaker, S, Henry, A P, Billington, C K, Shaw, D E, Johnson, S R, Benest, A V, Pang, V, Bates, D, Pogson, Z E K, Fogarty, A, McKeever, T M, Singapuri, A, Heaney, L, Mansur, A H, Chaudhuri, R, Thomson, N C, Holloway, J W, Lockett, G A, Howarth, P H, Niven, R, Simpson, A, Tobin, M D, Hall, I P, Wain, L V, Blakey, J D, Brightling, C E, Obeidat, M, Sin, D D, Nickle, C, Bossé, Y, Vonk, J M, van den Berge, M, Koppelman, G H, Sayers, Ian and Nawijn, Martijn C (2020) Phenotypic and functional translation of IL33 genetics in asthma. The Journal of allergy and clinical immunology. ISSN 1097-6825. (Submitted)

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Official URL: https://www.jacionline.org/article/S0091-6749(20)3...

Abstract

BACKGROUND

Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. Interleukin 33 (IL33) single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum, and bronchial biopsies of asthma patients. The functional consequences of IL33 asthma SNPs remain unknown.

OBJECTIVE

We studied whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. We 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/GASP cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modelling. Lentiviral overexpression was used to study IL33 effects on HBECs.

RESULTS

161 SNPs spanning the IL33 region associated with one or more asthma phenotypes after correction for multiple testing. We report one 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 FEV, FEV/FVC, atopy, and age of asthma onset. The two IL33 signals are expression quantitative loci (eQTLs) in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and ROS-capturing of HBECs, without influencing epithelial cell count, metabolic activity or barrier function.

CONCLUSION

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.

Item Type: Article
Subjects: WF Respiratory system. Respiratory medicine
Divisions: Emergency Services > Acute Medicine and AMU
Planned IP Care > Respiratory Medicine
Related URLs:
Depositing User: Mr Muneeb Liaquat
Date Deposited: 29 May 2020 16:17
Last Modified: 29 May 2020 16:17
URI: http://www.repository.uhblibrary.co.uk/id/eprint/3126

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