State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 195 Dongfeng Xi Road, Guangzhou, 510182, Guangdong, China.
Guangzhou National Laboratory, Guangzhou International BioIsland, No.9 XingDaoHuanBei Road, Guangzhou, 510005, Guangdong, China.
Cell Mol Life Sci. 2024 Aug 4;81(1):330. doi: 10.1007/s00018-024-05375-0.
Chronic obstructive pulmonary disease (COPD) is a complex syndrome with poorly understood mechanisms driving its early progression (GOLD stages 1-2). Elucidating the genetic factors that influence early-stage COPD, particularly those related to airway inflammation and remodeling, is crucial. This study analyzed lung tissue sequencing data from patients with early-stage COPD (GSE47460) and smoke-exposed mice. We employed Weighted Gene Co-Expression Network Analysis (WGCNA) and machine learning to identify potentially pathogenic genes. Further analyses included single-cell sequencing from both mice and COPD patients to pinpoint gene expression in specific cell types. Cell-cell communication and pseudotemporal analyses were conducted, with findings validated in smoke-exposed mice. Additionally, Mendelian randomization (MR) was used to confirm the association between candidate genes and lung function/COPD. Finally, functional validation was performed in vitro using cell cultures. Machine learning analysis of 30 differentially expressed genes identified 8 key genes, with CLEC5A emerging as a potential pathogenic factor in early-stage COPD. Bioinformatics analyses suggested a role for CLEC5A in macrophage-mediated inflammation during COPD. Two-sample Mendelian randomization linked CLEC5A single nucleotide polymorphisms (SNPs) with Forced Expiratory Volume in One Second (FEV1), FEV1/Forced Vital Capacity (FVC) and early/later on COPD. In vitro, the knockdown of CLEC5A led to a reduction in inflammatory markers within macrophages. Our study identifies CLEC5A as a critical gene in early-stage COPD, contributing to its pathogenesis through pro-inflammatory mechanisms. This discovery offers valuable insights for developing early diagnosis and treatment strategies for COPD and highlights CLEC5A as a promising target for further investigation.
慢性阻塞性肺疾病（COPD）是一种复杂的综合征，其早期进展的机制尚未被充分理解（GOLD 分期 1-2）。阐明影响早期 COPD 的遗传因素，特别是与气道炎症和重塑相关的因素，至关重要。本研究分析了早期 COPD 患者的肺组织测序数据（GSE47460）和吸烟暴露的小鼠。我们采用加权基因共表达网络分析（WGCNA）和机器学习来识别潜在的致病基因。进一步的分析包括来自小鼠和 COPD 患者的单细胞测序，以确定特定细胞类型中的基因表达。进行了细胞-细胞通讯和拟时分析，并在吸烟暴露的小鼠中进行了验证。此外，还使用孟德尔随机化（MR）来确认候选基因与肺功能/COPD 的关联。最后，在体外使用细胞培养进行了功能验证。对 30 个差异表达基因的机器学习分析确定了 8 个关键基因，其中 CLEC5A 是早期 COPD 的潜在致病因素。生物信息学分析表明，CLEC5A 在 COPD 期间巨噬细胞介导的炎症中发挥作用。两样本孟德尔随机化将 CLEC5A 单核苷酸多态性（SNP）与一秒用力呼气量（FEV1）、FEV1/用力肺活量（FVC）和早期/晚期 COPD 相关联。在体外，CLEC5A 的敲低导致巨噬细胞内炎症标志物减少。本研究确定 CLEC5A 是早期 COPD 的关键基因，通过促炎机制促进其发病机制。这一发现为 COPD 的早期诊断和治疗策略提供了有价值的见解，并凸显了 CLEC5A 作为进一步研究的有前途的靶点。
