Cross‐Compartment Multimodal Analyses Reveal Differences in IL2‐STAT5 Signaling Associated With Asthma in Individuals From Diverse Backgrounds

Self‐reported racial background has been associated with differences in asthma risk and severity, yet detailed insights remain limited. Non‐European American (EA)/non‐White populations are considerably underrepresented in this context. To address this gap, we performed multimodal analyses across various compartments in healthy individuals and asthma patients, interrogating potential differences related to self‐reported racial background. During asthma, self‐reported African American (AA) patients exhibited higher IL2‐STAT5 signaling, a key pathway in asthma pathophysiology, across bronchial and airway epithelium, circulating CD4 + T cells, whole blood, and peripheral blood mononuclear cells (PBMCs). This correlated with increased T cell activation and recruitment, processes central to asthma development. In healthy AA, compared to EA individuals, CITE‐seq, scRNA‐seq, and phospho‐CyTOF analyses revealed elevated IL2‐STAT5 signaling in PBMCs and lung‐derived immune cells, suggesting potentially heightened predispositions toward asthma. Together, these findings provide initial insights suggesting self‐reported racial background‐related differences in immune pathways relevant to asthma, highlighting the functional implication of IL2‐STAT5 signaling. If validated in larger and more diverse cohorts, these insights may inform risk stratification strategies and targeted therapeutic approaches. Our results highlight the urgent need for broader representation of diverse background populations in asthma research to advance more equitable and biologically informed precision medicine.