Multicohort Analysis of Bronchial Epithelial Cell Expression in Healthy Subjects and Patients with Asthma Reveals Four Clinically Distinct Clusters.

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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 (BEC) samples across 11 independent cohorts, including 3 cohorts from the Severe Asthma Research Program (SARP). Using 7 datasets (218 asthma patients, 148 healthy controls) as discovery cohorts, we identified 505 differentially expressed genes (DEGs), which we validated in the remaining four datasets. Unsupervised clustering using the 505 DEGs identified four reproducible clusters of patients with asthma across all datasets corresponding to healthy controls, mild/moderate asthma, and severe asthma with significant differences in several clinical markers of severity, including pulmonary function, T2 inflammation, FeNO, and max 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 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 asthma patients most likely to benefit.