Phenotypic and functional translation of IL33 genetics in asthma
Phenotypic and functional translation of IL33 genetics in asthma
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DOI：
10.1016/j.jaci.2020.04.051
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发表时间：
2021-01-05
影响因子：
14.2
通讯作者：
Nawijn, Martijn C.
中科院分区：
文献类型：
--
作者：
Ketelaar, Maria E.;Portelli, Michael A.;Nawijn, Martijn C.
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上可能有所不同。IL33单核苷酸多态(SNPs)与哮喘相关。哮喘患者痰和支气管活检组织中IL33水平升高。IL33单核苷酸多态性对哮喘的功能影响尚不清楚。目的：本研究试图确定IL33单核苷酸多态性是否与哮喘相关的表型以及IL33在肺或支气管上皮中的表达有关。方法：采用回归模型分析IL33单核苷酸多态(CHR9：5,815,7866,657,983)与哮喘表型(LIFLINS/DAG[荷兰哮喘患者组]/GAP[哮喘严重程度和表型遗传]队列)以及SNPs与哮喘表达(肺组织、支气管刷毛、HBEC)之间的关系。用慢病毒过表达来研究IL33对HBEC的影响。结果：我们发现161个跨越IL33区域的SNPs与一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，该信号与血中嗜酸粒细胞水平、哮喘和嗜酸性哮喘有关。由rs4008366标记的第二个独立信号与嗜酸性哮喘的相关性不大。与FEV1、FEV1/用力肺活量、特应性和哮喘发病年龄无关的信号。这2个IL33信号是在支气管刷和培养的HBECs中表达的定量位点，而在肺组织中不表达。结论：我们发现IL33是嗜酸性粒细胞增多症和哮喘的上皮性易感基因，并提示IL33通路在嗜酸性哮喘中具有靶向性。
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: 5,815,7866,657,983) 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.