Zhao Lu, Gao Jiali, Chen Gongqi, Huang Chunli, Kong Weiqiang, Feng Yuchen, Zhen Guohua
Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Key Laboratory of Respiratory Diseases, National Health Commission of People's Republic of China, Wuhan, China.
Front Genet. 2023 Apr 21;14:1186317. doi: 10.3389/fgene.2023.1186317. eCollection 2023.
Type 2 (T2)-low asthma can be severe and corticosteroid-resistant. Airway epithelial cells play a pivotal role in the development of asthma, and mitochondria dysfunction is involved in the pathogenesis of asthma. However, the role of epithelial mitochondria dysfunction in T2-low asthma remains unknown. Differentially expressed genes (DEGs) were identified using gene expression omnibus (GEO) dataset GSE4302, which is originated from airway epithelial brushings from T2-high (n = 22) and T2-low asthma patients (n = 20). Gene set enrichment analysis (GSEA) was implemented to analyze the potential biological pathway involved between T2-low and T2-high asthma. T2-low asthma related genes were identified using weighted gene co-expression network analysis (WGCNA). The mitochondria-related genes (Mito-RGs) were referred to the Molecular Signatures Database (MSigDB). T2-low asthma related mitochondria (T2-low-Mito) DEGs were obtained by intersecting the DEGs, T2-low asthma related genes, and Mito-RGs. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was performed to further explore the potential function of the T2-low-Mito DEGs. In addition, the hub genes were further identified by protein-protein interaction (PPI), and the expressions of hub genes were verified in another GEO dataset GSE67472 and bronchial brushings from patients recruited at Tongji Hospital. Six hundred and ninety-two DEGs, including 107 downregulated genes and 585 upregulated genes were identified in airway epithelial brushings from T2-high and T2-low asthma patients included in GSE4302 dataset. GSEA showed that mitochondrial ATP synthesis coupled electron transport is involved in T2-low asthma. Nine hundred and four T2-low asthma related genes were identified using WGCNA. Twenty-two T2-low-Mito DEGs were obtained by intersecting the DEGs, T2-low asthma and Mito-RGs. The GO enrichment analysis of the T2-low-Mito DEGs showed significant enrichment of mitochondrial respiratory chain complex assembly, and respiratory electron transport chain. PPI network was constructed using 22 T2-low-Mito DEGs, and five hub genes, , , , , and , were identified. Moreover, the expression of these hub genes was validated in another GEO dataset, and our cohort of asthma patients. This study suggests that mitochondria dysfunction contributes to T2-low asthma.
2型（T2）-低哮喘可能较为严重且对皮质类固醇耐药。气道上皮细胞在哮喘的发生发展中起关键作用，线粒体功能障碍参与哮喘的发病机制。然而，上皮线粒体功能障碍在T2-低哮喘中的作用尚不清楚。使用基因表达综合数据库（GEO）数据集GSE4302鉴定差异表达基因（DEG），该数据集源自T2-高（n = 22）和T2-低哮喘患者（n = 20）的气道上皮刷检样本。实施基因集富集分析（GSEA）以分析T2-低哮喘和T2-高哮喘之间潜在的生物学途径。使用加权基因共表达网络分析（WGCNA）鉴定T2-低哮喘相关基因。线粒体相关基因（Mito-RG）参考分子特征数据库（MSigDB）。通过将DEG、T2-低哮喘相关基因和Mito-RG相交，获得T2-低哮喘相关线粒体（T2-低-Mito）DEG。进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析以进一步探索T2-低-Mito DEG的潜在功能。此外，通过蛋白质-蛋白质相互作用（PPI）进一步鉴定枢纽基因，并在另一个GEO数据集GSE67472和同济医院招募患者的支气管刷检样本中验证枢纽基因的表达。在GSE4302数据集中纳入的T2-高和T2-低哮喘患者的气道上皮刷检样本中，鉴定出692个DEG，包括107个下调基因和585个上调基因。GSEA显示线粒体ATP合成偶联电子传递参与T2-低哮喘。使用WGCNA鉴定出904个T2-低哮喘相关基因。通过将DEG、T2-低哮喘相关基因和Mito-RG相交，获得22个T2-低-Mito DEG。T2-低-Mito DEG的GO富集分析显示线粒体呼吸链复合物组装和呼吸电子传递链显著富集。使用22个T2-低-Mito DEG构建PPI网络，鉴定出5个枢纽基因，分别为 、 、 、 、 和 。此外,这些枢纽基因的表达在另一个GEO数据集和我们的哮喘患者队列中得到验证。本研究表明线粒体功能障碍导致T2-低哮喘。
