Phenotypic and functional translation of IL33 genetics in asthma.,Journal of Allergy and Clinical Immunology

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Phenotypic and functional translation of IL33 genetics in asthma.
Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2020-05-19 , DOI: 10.1016/j.jaci.2020.04.051
Maria E Ketelaar ₁ , Michael A Portelli ₂ , F Nicole Dijk ₃ , Nick Shrine ₄ , Alen Faiz ₅ , Cornelis J Vermeulen ₅ , Cheng J Xu ₆ , Jenny Hankinson ₇ , Sangita Bhaker ₂ , Amanda P Henry ₂ , Charlote K Billington ₂ , Dominick E Shaw ₂ , Simon R Johnson ₂ , Andrew V Benest ₈ , Vincent Pang ₈ , David O Bates ₈ , Z E K Pogson ₉ , Andrew Fogarty ₁₀ , Tricia M McKeever ₁₀ , Amisha Singapuri ₁₁ , Liam G Heaney ₁₂ , Adel H Mansur ₁₃ , Rekha Chaudhuri ₁₄ , Neil C Thomson ₁₄ , John W Holloway ₁₅ , Gabrielle A Lockett ₁₅ , Peter H Howarth ₁₅ , Robert Niven ₇ , Angela Simpson ₇ , Martin D Tobin ₄ , Ian P Hall ₂ , Louise V Wain ₄ , John D Blakey ₁₆ , Christopher E Brightling ₁₇ , Ma'en Obeidat ₁₈ , Don D Sin ₁₉ , David C Nickle ₂₀ , Yohan Bossé ₂₁ , Judith M Vonk ₂₂ , Maarten van den Berge ₂₃ , Gerard H Koppelman ₃ , Ian Sayers ₂ , Martijn C Nawijn ₂₄

Affiliation

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, Groningen, The Netherlands; Department of Pathology and Medical Biology, 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, University of Nottingham, Nottingham, United Kingdom.
Division of Respiratory Medicine, National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.
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, Groningen, The Netherlands.
Department of Health Sciences, University of Leicester, Leicester, United Kingdom; National Institute for Health Research Leicester Respiratory Biomedical Research Centre, Leicester, United Kingdom.
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.
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, Groningen, The Netherlands; CiiM & TWINCORE, Helmholtz-Centre for Infection Research and the Hannover Medical School, Hannover, Germany.
Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.
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.
Department of Respiratory Medicine, Lincoln County Hospital, Lincoln, United Kingdom; Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom.
Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom.
Institute for Lung Health, Department of Respiratory Sciences, Glenfield Hospital, University of Leicester, Leicester, United Kingdom.
Centre for Infection and Immunity, Queen's University of Belfast, Belfast, United Kingdom.
Respiratory Medicine, Birmingham Heartlands Hospital and University of Birmingham, Birmingham, United Kingdom.
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
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 Southampton, Southampton, United Kingdom.
Respiratory Medicine, Sir Charles Gairdner Hospital, Perth, Australia.
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.
The Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
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.
Department of Genetics and Pharmacogenomics, Merck Research Laboratories, Boston, Mass.
Department of Molecular Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Quebec City, Quebec, Canada.
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.
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, University of Nottingham, Nottingham, United Kingdom.
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.

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.

中文翻译：

IL33遗传学在哮喘中的表型和功能翻译。

背景

哮喘是一种复杂的疾病，具有多种表型，在疾病病理生物学和治疗反应方面可能不同。IL33单核苷酸多态性 (SNP) 与哮喘具有可重复性相关。哮喘患者的痰液和支气管活检中 IL33 水平升高。IL33哮喘 SNP的功能后果仍然未知。

客观的

本研究旨在确定IL33 SNP 是否与哮喘相关表型以及肺或支气管上皮细胞中的IL33表达相关。本研究调查了增加的IL33表达对人支气管上皮细胞 (HBEC) 功能的影响。

方法

IL33 SNP（Chr9：5,815,786-6,657,983）与哮喘表型（Lifelines/DAG [荷兰哮喘 GWAS]/GASP [哮喘严重程度和表型的遗传学] 队列）之间以及 SNP 与表达（肺组织、支气管刷、HBEC）之间的关联是使用回归模型完成。慢病毒过表达用于研究IL33 对HBEC 的影响。

结果

我们发现，经过多次测试校正后，跨越IL33区域的 161 个 SNP 与 1 种或多种哮喘表型相关。我们报告了一个由 rs992969 标记的主要独立信号，与血液嗜酸性粒细胞水平、哮喘和嗜酸性粒细胞性哮喘相关。由 rs4008366 标记的第二个独立信号与嗜酸性粒细胞性哮喘有适度关联。信号均与 FEV ₁、FEV ₁ /用力肺活量、特应性和哮喘发作年龄无关。2 个 IL33 信号是支气管刷和培养的HBEC中的表达定量基因座，但在肺组织中没有。IL33体外过表达导致 HBEC 的活力和活性氧物种捕获降低，而不影响上皮细胞计数、代谢活性或屏障功能。