Asthma and lower airway diseasePhenotypic and functional translation of IL33 genetics in asthma
Graphical abstract
Section snippets
Methods
Detailed methods are described in this article’s Online Repository at www.jacionline.org. The analysis codes are available at https://git.web.rug.nl/P252222/IL33_Ketelaaretal_JACI2020.
The IL33 locus particularly associates with eosinophilia and eosinophilic asthma
Overall in DAG/GASP and Lifelines, 161 SNPs significantly associated with 1 or more asthma phenotypes (Padj < .05 FDR) (see Tables E11 to E15 in this article’s Online Repository at www.jacionline.org) and were mainly derived from the Lifelines cohort. From these, 144 SNPs composed of 5 LD blocks (A-E, r2 > 0.1). Markedly, these 5 LD blocks all associated with an eosinophilic phenotype—with blood eosinophil counts, eosinophilic asthma, and/or asthma (Table I, and see Tables E11-E17 and Figs E2
Discussion
We set out to determine whether SNPs in the IL33 region associate with specific phenotypes of asthma, whether these regulate IL33 expression in lung tissue or bronchial epithelial samples, and whether increased IL33 expression alters HBEC biology. Genetic signals at the IL33 locus predominantly associate with an eosinophilic phenotype in the general population and asthma subjects, whereby the IL33 risk allele is associated with higher IL33 expression in vivo. Using conditional analyses, we
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2022, Immunology and Allergy Clinics of North AmericaCitation Excerpt :IL-33 levels are increased in asthma with bronchial epithelial cells as an important source. A role in asthma pathophysiology is supported by genome association studies.29,30 A phase 2a clinical trial of anti-IL-33 in asthma was positive for a reduction in loss of control events.31
This study was supported by Lung Foundation Netherlands grants AF 95.05 (G.H.K.), AF 98.48 (G.H.K.), and AF3.2.09.081JU (G.H.K., M.C.N.), the University Medical Center Groningen (G.H.K.), Dutch TerMeulen Fund (M.E.K.), the Ubbo Emmius Foundation (G.H.K.), and a grant from GlaxoSmithKline (I.S., I.H., M.C.N., G.H.K.). 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; the University Medical Center Groningen; University Groningen; and the Northern Provinces of the Netherlands. The generation of the lung tissue dataset was funded by Merck. This study was also funded by an Asthma UK grant AUK-PG-2013-188 (I.S., I.P.H., D.E.S., C.E.B.) and additional funding by Asthma UK grants 10/006 and 11/031 (I.S., D.E.S.). Genotyping in GASP (Genetics of Asthma Severity & Phenotypes) cohort was additionally supported by Rosetrees Trust (I.S.) and AirPROM (C.E.B., M.T., I.S.). This work was supported by the Medical Research Council grant MC_PC_12010, a Strategic Award (I.P.H., M.D.T., L.V.W.), and Medical Research Council project grant G1100163 (S.R.J.). L.V.W. holds the GSK/British Lung Foundation Chair in Respiratory Research. Asthma UK funded the GASP Initiative (grant AUK-PG-2013-188). This work was part funded by the National Institute for Health Research Leicester Respiratory Biomedical Centre. A.S. is supported by the Manchester Biomedical Research Centre.
Disclosure of potential conflict of interest: G.H. Koppelman, M.C. Nawijn, M.E. Ketelaar, C.J. Xu, M.A. Portelli, I. Sayers, and I.P. Hall report research funding from GlaxoSmithKline relating to this manuscript. I. Sayers has had research funding relating to this manuscript from AnaptysBio Inc. J.D. Blakely reports personal fees and nonfinancial support from Napp, personal fees from Novartis, personal fees and nonfinancial support from Astra Zeneca, personal fees and nonfinancial support from Boehringer Ingelheim, personal fees from Teva, and personal fees from Innovate UK, outside the submitted work. S.R. Johnson reports grants from Medical Research Council, during the conduct of the study, and nonfinancial support from Boehringer-Ingelheim, outside the submitted work. C.E. Brightling reports grants from AirPROM FP7, grants from Asthma UK, and grants from National Institute for Health Research Biomedical Research Centre, during the conduct of the study. D.E. Shaw reports grants from GlaxoSmithKline, during the conduct of the study, and grants from GlaxoSmithKline, outside the submitted work. G.H. Koppelman reports grants from TEVA the Netherlands, Vertex, and Stichting Astma Bestrijding, outside the submitted work, and advisory board fees from GlaxoSmithKline and PureIMS, outside the submitted work. M.C. Nawijn reports grants from GlaxoSmithKline, outside the submitted work. I. Sayers reports grants from GlaxoSmithKline and grants from Anaptsbio Inc, outside the submitted work. R. Chaudhuri reports personal fees and nonfinancial support from AstraZeneca, personal fees from GlaxoSmithKline, personal fees from Teva Pharmaceuticals, and personal fees and nonfinancial support from Novartis, outside the submitted work. A.V. Benest and D.O. Bates are supported by British Heart Foundation grant. A.V. Benest is supported by a Royal Society Project grant RGS∖R1∖191221. The remaining authors have declared that no conflict of interest exists.
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These authors contributed equally and are co-first authors.
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These authors contributed equally and are co-last authors.