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Phenotypic and functional translation of IL33 genetics in asthma.
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.
Affiliation
  • Ketelaar ME; Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Gronin
  • Portelli MA; Division of Respiratory Medicine, National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.
  • Dijk FN; Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Gronin
  • Shrine N; Department of Health Sciences, University of Leicester, Leicester, United Kingdom; National Institute for Health Research Leicester Respiratory Biomedical Research Centre, Leicester, United Kingdom.
  • Faiz A; Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
  • Vermeulen CJ; Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
  • Xu CJ; Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Gronin
  • Hankinson J; Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.
  • Bhaker S; Division of Respiratory Medicine, National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.
  • Henry AP; Division of Respiratory Medicine, National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.
  • Billington CK; Division of Respiratory Medicine, National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.
  • Shaw DE; Division of Respiratory Medicine, National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.
  • Johnson SR; Division of Respiratory Medicine, National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.
  • Benest AV; Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, and COMPARE University of Birmingham and University of Nottingham, Nottingham, United Kingdom.
  • Pang V; Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, and COMPARE University of Birmingham and University of Nottingham, Nottingham, United Kingdom.
  • Bates DO; Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, and COMPARE University of Birmingham and University of Nottingham, Nottingham, United Kingdom.
  • Pogson ZEK; Department of Respiratory Medicine, Lincoln County Hospital, Lincoln, United Kingdom; Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom.
  • Fogarty A; Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom.
  • McKeever TM; Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom.
  • Singapuri A; Institute for Lung Health, Department of Respiratory Sciences, Glenfield Hospital, University of Leicester, Leicester, United Kingdom.
  • Heaney LG; Centre for Infection and Immunity, Queen's University of Belfast, Belfast, United Kingdom.
  • Mansur AH; Respiratory Medicine, Birmingham Heartlands Hospital and University of Birmingham, Birmingham, United Kingdom.
  • Chaudhuri R; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
  • Thomson NC; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
  • Holloway JW; Human Development and Health, Faculty of Medicine and National Institute of Health Biomedical Research Centre, University of Southampton, Southampton, United Kingdom; Clinical and Experimental Sciences, Faculty of Medicine and National Institute of Health Biomedical Research Centre, University of So
  • Lockett GA; Human Development and Health, Faculty of Medicine and National Institute of Health Biomedical Research Centre, University of Southampton, Southampton, United Kingdom; Clinical and Experimental Sciences, Faculty of Medicine and National Institute of Health Biomedical Research Centre, University of So
  • Howarth PH; Human Development and Health, Faculty of Medicine and National Institute of Health Biomedical Research Centre, University of Southampton, Southampton, United Kingdom; Clinical and Experimental Sciences, Faculty of Medicine and National Institute of Health Biomedical Research Centre, University of So
  • Niven R; Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.
  • Simpson A; Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.
  • Tobin MD; Department of Health Sciences, University of Leicester, Leicester, United Kingdom; National Institute for Health Research Leicester Respiratory Biomedical Research Centre, Leicester, United Kingdom.
  • Hall IP; Division of Respiratory Medicine, National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.
  • Wain LV; Department of Health Sciences, University of Leicester, Leicester, United Kingdom; National Institute for Health Research Leicester Respiratory Biomedical Research Centre, Leicester, United Kingdom.
  • Blakey JD; Respiratory Medicine, Sir Charles Gairdner Hospital, Perth, Australia.
  • Brightling CE; National Institute for Health Research Leicester Respiratory Biomedical Research Centre, Leicester, United Kingdom; Institute for Lung Health, Department of Respiratory Sciences, Glenfield Hospital, University of Leicester, Leicester, United Kingdom.
  • Obeidat M; The Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
  • Sin DD; The Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada; Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
  • Nickle DC; Department of Genetics and Pharmacogenomics, Merck Research Laboratories, Boston, Mass.
  • Bossé Y; Department of Molecular Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Quebec City, Quebec, Canada.
  • Vonk JM; Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
  • van den Berge M; Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Division of Respiratory Medicine, National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Biodiscovery Institute, Un
  • Koppelman GH; Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Gronin
  • Sayers I; Division of Respiratory Medicine, National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.
  • Nawijn MC; Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
J Allergy Clin Immunol ; 147(1): 144-157, 2021 01.
Article in En | MEDLINE | ID: mdl-32442646
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Asthma / Gene Expression Regulation / Genetic Predisposition to Disease / Polymorphism, Single Nucleotide / Interleukin-33 Limits: Adult / Female / Humans / Male / Middle aged Language: En Journal: J Allergy Clin Immunol Year: 2021 Type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Asthma / Gene Expression Regulation / Genetic Predisposition to Disease / Polymorphism, Single Nucleotide / Interleukin-33 Limits: Adult / Female / Humans / Male / Middle aged Language: En Journal: J Allergy Clin Immunol Year: 2021 Type: Article