Lee Ian, Ganesan Ananthakrishnan, Kalesinskas Laurynas, Zheng Hong, Ahn Haejun C, Christenson Stephanie, Erzurum Serpil C, Zein Joe, Bleecker Eugene R, Meyers Deborah A, Castro Mario, Fahy John V, Israel Elliot, Jarjour Nizar N, Moore Wendy C, Wenzel Sally E, Mauger David T, Levy Bruce D, Woodruff Prescott G, Ortega Victor E, Khatri Purvesh
Institute for Immunity Transplantation and Infection, Stanford, California.
Center for Biomedical Informatics Research, Department of Medicine.
Am J Respir Cell Mol Biol. 2025 Jul;73(1):73-87. doi: 10.1165/rcmb.2024-0125OC.
Asthma is a heterogeneous disease with variable presentation and characteristics. There is a critical need to identify underlying molecular endotypes of asthma. We performed the largest transcriptomic analysis of 808 bronchial epithelial cell samples across 11 independent cohorts, including 3 cohorts from the Severe Asthma Research Program. Using seven datasets (218 patients with asthma, 148 healthy control subjects) as discovery cohorts, we identified 505 differentially expressed genes, which we validated in the remaining four datasets. Unsupervised clustering using the 505 differentially expressed genes identified four reproducible clusters of patients with asthma across all datasets, corresponding to healthy control subjects, patients with mild/moderate asthma, and patients with severe asthma with significant differences in several clinical markers of severity, including pulmonary function, Type 2 inflammation, fractional exhaled nitric oxide, and maximum bronchodilator reversibility. Importantly, we found the same clusters in pediatric patients using nasal lavage fluid cells, demonstrating the gene signature and clusters are not confounded by age and are conserved in both lower and upper airways. The four asthma clusters may represent a unifying framework for understanding the molecular heterogeneity of asthma. Further study could potentially enable a precision medicine approach of matching therapies with patients with asthma most likely to benefit.
哮喘是一种具有多种表现形式和特征的异质性疾病。迫切需要确定哮喘潜在的分子内型。我们对来自11个独立队列的808份支气管上皮细胞样本进行了最大规模的转录组分析，其中包括来自重症哮喘研究项目的3个队列。我们使用7个数据集（218例哮喘患者、148例健康对照者）作为发现队列，鉴定出505个差异表达基因，并在其余4个数据集中进行了验证。使用这505个差异表达基因进行无监督聚类，在所有数据集中识别出4个可重复的哮喘患者聚类，分别对应健康对照者、轻/中度哮喘患者和重度哮喘患者，这些聚类在包括肺功能、2型炎症、呼出一氧化氮分数和最大支气管扩张剂可逆性等几个严重程度临床指标上存在显著差异。重要的是，我们在儿科患者的鼻腔灌洗液细胞中发现了相同的聚类，表明该基因特征和聚类不受年龄影响，并且在下呼吸道和上呼吸道中均保守。这4个哮喘聚类可能代表了一个理解哮喘分子异质性的统一框架。进一步的研究可能会促成一种精准医学方法，将治疗与最可能受益的哮喘患者相匹配。
