Abstract Introduction Approximately 39% of asthma patients are obese and experience worse control, quality of life, and more frequent exacerbations. There is an urgent need for therapies to control obese asthma as current therapies specifically target type 2 inflammation, failing to remediate obesity-induced pathogenic inflammation via alternate mechanisms. Methods We analyzed bulk airway epithelial cell (AEC) RNASeq data from endobronchial brushings in two deeply phenotyped asthma cohorts: 1) Severe Asthma Research Program (SARP; N = 156 discovery); and 2) Immune Mechanisms in Severe Asthma (IMSA; N = 67 replication). Obesity was defined as BMI≥30 kg/m² and normal weight as 18.5BMI25 kg/m2. To capture both categorical and graded effects of obesity on lung biology, differential gene expression analyses were conducted using two related outcomes: 1) Obese vs. normal weight asthma (excluding underweight/overweight; SARP N = 107, IMSA N = 46), and 2) Continuous BMI across all participants (SARP N = 156, IMSA N = 67).Models were adjusted for age, sex, race, batch, and surrogate variables capturing latent technical artifacts. Significance was defined as Q 0.05 for discovery and P 0.05 for replication. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify obesity-associated modules of co-expressed genes, which were tested for cross-cohort preservation. Gene set enrichment and drug repurposing were performed on replicated genes and significant WGCNA modules. Relative abundances of AEC subtypes from bulk RNASeq were estimated using CIBERSORTx with a single-cell reference matrix. Results Obesity prevalence was similar in SARP (39.1%) and IMSA (41.7%). In SARP, 502 genes were associated with obese vs. normal weight asthma and 1,046 genes with BMI. Five obesity-associated and 76 BMI-associated genes identified in SARP replicated in IMSA, and were enriched for extracellular matrix remodeling, submucosal gland biology, and skeletal muscle processes. Seven replicated BMI-associated genes (ANG, B4GALT2, CCR5, CHRM1, DGAT1, G6PD, SLC7A1) had existing druggable targets. One WGCNA module negatively correlated with obesity (r = −0.27, P = 0.003) and was enriched for genes involved in GPCR, hypoxia, and calcium signaling. Cross-cohort module preservation analysis revealed significant overlap between one SARP and one IMSA module (N = 58 overlapping genes; Q = 3.6E-108), both of which were associated with obesity. The overlapping 58 genes were significantly enriched for adipogenesis, DNA methylation, and cellular senescence, demonstrating robust obesity-related asthma network perturbations. Obesity was associated with lower club and higher goblet cell proportions compared to normal weight. Conclusions We identified reproducible single-gene and network-level signatures of obesity-associated asthma. These findings highlight immune-metabolic pathways and druggable targets that may inform precision therapies for this increasingly prevalent asthma endotype. This abstract is funded by: NIH
Wilson et al. (Fri,) studied this question.