Phenotypic and functional translation of IL33 genetics in asthma.
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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 V, Pang Vincent, Bates David O, Pogson Z 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, Bossé Yohan, Vonk Judith M, van den Berge Maarten, Koppelman Gerard H, Sayers Ian, Nawijn Martijn C
Аннотация
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.