Phenotypic and functional translation of IL33 genetics in asthma

Maria E Ketelaar, Michael A Portelli, F Nicole Dijk, N Shrine, A Faiz, C J Vermeulen, C J Xu, J Hankinson, S Bhaker, A P Henry, C K Billington, D E Shaw, S R Johnson, A V Benest, V Pang, D Bates, Z E K Pogson, A Fogarty, T M McKeever, A SingapuriL Heaney, A H Mansur, R Chaudhuri, N C Thomson, J W Holloway, G A Lockett, P H Howarth, R Niven, A Simpson, M D Tobin, I P Hall, L V Wain, J D Blakey, C E Brightling, M Obeidat, D D Sin, C Nickle, Y Bossé, J M Vonk, M van den Berge, G H Koppelman, Ian Sayers, Martijn C Nawijn

Research output: Contribution to journalArticle

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 FEV1, FEV1/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.

Original languageEnglish
JournalThe Journal of Allergy and Clinical Immunology
DOIs
Publication statusE-pub ahead of print - 19 May 2020

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