Phenotypic and functional translation of IL33 genetics in asthma

Maria E. Ketelaar*, Michael A. Portelli, F. Nicole Dijk, Nick Shrine, Alen Faiz, Cornelis J. Vermeulen, Cheng J. Xu, Jenny Hankinson, Sangita Bhaker, Amanda P. Henry, Charlote K. Billington, Dominick E. Shaw, Simon R. Johnson, Andrew V. Benest, Vincent Pang, David O. Bates, Z. E.K. Pogson, Andrew Fogarty, Tricia M. McKeever, Amisha SingapuriLiam G. Heaney, Adel H. Mansur, Rekha Chaudhuri, Neil C. Thomson, John W. Holloway, Gabrielle A. Lockett, Peter H. Howarth, Robert Niven, Angela Simpson, Martin D. Tobin, Ian P. Hall, Louise V. Wain, John D. Blakey, Christopher E. Brightling, Ma'en Obeidat, Don D. Sin, David C. Nickle, Yohan Bossé, Judith M. Vonk, Maarten van den Berge, Gerard H. Koppelman, Ian Sayers, Martijn C. Nawijn

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)144-157
Number of pages14
JournalJournal of Allergy and Clinical Immunology
Volume147
Issue number1
Early online date19 May 2020
DOIs
Publication statusPublished - Jan 2021

Bibliographical note

Funding Information:
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.

Funding Information:
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 .

Funding Information:
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.

Publisher Copyright:
© 2020

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

  • asthma phenotypes
  • bronchial epithelium
  • eQTL
  • functional translation
  • IL33 SNPs

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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