Molecular Phenotyping Based on Blood Transcriptome-Associated Clusters in Asthma: Findings From Two Korean Asthma Cohorts

Abstract

Purpose: Asthma is heterogeneous in its molecular and clinical manifestations, complicating treatment. In this study, we investigated the molecular phenotypes of asthma using RNA-sequencing (RNA-seq) of peripheral blood mononuclear cells to advance precision medicine approaches. Methods: We analyzed peripheral blood RNA-seq data from 456 participants from the Cohort for Reality and Evolution of Adult Asthma in Korea, including 23 patients with severe asthma and 433 with non-severe asthma to identify blood transcriptome-associated clusters (B-TACs) that correlate with distinct inflammatory processes. This included a meta-analysis of differentially expressed genes to refine gene selection for defining B-TACs. Gene Set Variation Analysis was used to assess the differential activation of biological pathways across B-TACs. We validated these findings in the Precision Medicine Intervention in Severe Asthma cohort of 122 patients, focusing on cluster stability, clinical correlates, and treatment responsiveness. Results: Our analysis identified 3 B-TACs (B-TAC1, B-TAC2 and B-TAC3) with B-TAC1 and B-TAC2 showing higher blood eosinophil levels than B-TAC3. B-TAC1 was characterized by a clear T2-high inflammatory profile, whereas B-TAC2 exhibited a mixed molecular phenotype with both T2-high and non-T2 features. B-TAC3 was associated with low T2 and inflammasome-related inflammation profiles. Validation using the PRISM cohort underscored the stability of B-TAC1 and B-TAC2. Notably, patients with B-TAC2 molecular phenotype had lower biologics use and tended to have less favorable treatment outcomes than those with B-TAC1. Conclusions: We discovered and validated 3 B-TACs, with B-TAC2 displaying a mixed T2-high and non-T2 phenotype, suggesting a potential reduction in responsiveness to biologic treatments. These findings provide molecular insights that may guide the development of personalized treatment strategies for asthma.