T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED
T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED
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DOI：
10.1183/13993003.02135-2016
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发表时间：
2017-02-01
影响因子：
24.3
通讯作者：
Chung, Kian Fan
中科院分区：
文献类型：
--
作者：
Kuo, Chih-Hsi Scott;Pavlidis, Stelios;Chung, Kian Fan
哮喘的特征在于异质性临床表型。我们的目的是通过分析104名中重度哮喘患者和16名非哮喘患者的痰细胞转录组学来确定哮喘的分子表型。在筛选嗜酸性粒细胞相关和非嗜酸性粒细胞相关痰炎症之间的差异表达基因后，我们对508个差异表达基因进行了无偏的层次聚类，并对特定基因集进行了基因集变异分析。相关簇（TAC）：TAC 1（以免疫受体IL 33 R、CCR 3和TSLPR为特征）、TAC 2（以干扰素、肿瘤坏死因子-α和炎性小体相关基因为特征）和TAC 3（以代谢途径、泛素化和线粒体功能的基因为特征）。TAC 1表现出白细胞介素-13/辅助性T细胞2型（Th 2）和先天性淋巴细胞2型的基因特征的最高富集。TAC 1的痰嗜酸性粒细胞和呼出气一氧化氮分数最高，仅限于严重哮喘伴口服皮质类固醇依赖、频繁加重和严重气流阻塞。TAC 2组痰嗜中性粒细胞、血清C反应蛋白水平和湿疹患病率最高。TAC 3具有正常至中度高的痰嗜酸性粒细胞，并且在1秒内更好地保留了用力呼气量。TAC 1和TAC 2的基因-蛋白共表达网络扩展了这一分子分类，我们定义了一种Th 2-高嗜酸性表型TAC 1，以及两种非Th 2表型TAC 2和TAC 3，其特征分别为炎性小体相关和代谢/线粒体途径。
Asthma is characterised by heterogeneous clinical phenotypes. Our objective was to determine molecular phenotypes of asthma by analysing sputum cell transcriptomics from 104 moderate-to-severe asthmatic subjects and 16 nonasthmatic subjects.After filtering on the differentially expressed genes between eosinophil-and noneosinophil-associated sputum inflammation, we used unbiased hierarchical clustering on 508 differentially expressed genes and gene set variation analysis of specific gene sets.We defined three transcriptome-associated clusters (TACs): TAC1 (characterised by immune receptors IL33R, CCR3 and TSLPR), TAC2 (characterised by interferon-, tumour necrosis factor-alpha- and inflammasome-associated genes) and TAC3 (characterised by genes of metabolic pathways, ubiquitination and mitochondrial function). TAC1 showed the highest enrichment of gene signatures for interleukin-13/T-helper cell type 2 (Th2) and innate lymphoid cell type 2. TAC1 had the highest sputum eosinophilia and exhaled nitric oxide fraction, and was restricted to severe asthma with oral corticosteroid dependency, frequent exacerbations and severe airflow obstruction. TAC2 showed the highest sputum neutrophilia, serum C-reactive protein levels and prevalence of eczema. TAC3 had normal to moderately high sputum eosinophils and better preserved forced expiratory volume in 1 s. Gene-protein coexpression networks from TAC1 and TAC2 extended this molecular classification.We defined one Th2-high eosinophilic phenotype TAC1, and two non-Th2 phenotypes TAC2 and TAC3, characterised by inflammasome- associated and metabolic/mitochondrial pathways, respectively.