哮喘中 IL33 遗传学的表型和功能转化。

Phenotypic and functional translation of IL33 genetics in asthma.

机构信息

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.

出版信息

J Allergy Clin Immunol. 2021 Jan;147(1):144-157. doi: 10.1016/j.jaci.2020.04.051. Epub 2020 May 19.

DOI:10.1016/j.jaci.2020.04.051

PMID: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 FEV, FEV/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.

摘要

背景

哮喘是一种具有多种表型的复杂疾病，其疾病病理生物学和治疗反应可能有所不同。白细胞介素 33（IL33）单核苷酸多态性（SNP）已被反复证明与哮喘相关。哮喘患者的痰和支气管活检中 IL33 水平升高。IL33 哮喘 SNP 的功能后果仍不清楚。

目的

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

使用回归建模分析 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。使用慢病毒过表达研究 IL33 对 HBEC 的影响。

结果

我们发现，在进行多次检验校正后，跨越 IL33 区域的 161 个 SNP 与 1 个或多个哮喘表型相关。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。第二个由 rs4008366 标记的独立信号与嗜酸性粒细胞性哮喘呈弱相关。这两个信号均与 FEV、FEV/用力肺活量、过敏和哮喘发病年龄无关。这 2 个 IL33 信号是支气管刷和培养的 HBEC 中的表达数量性状基因座，但不是在肺组织中。体外过表达 IL33 导致 HBEC 活力降低和活性氧捕获，而不影响上皮细胞计数、代谢活性或屏障功能。