Genetic susceptibility to PM2.5 exposure drives transcriptional responses in pediatric asthma: insights from single-cell transcriptomics

Background. Exposure to fine particulate matter (PM2.5) increases asthma severity and reduces glucocorticoid responsiveness in children, yet the molecular mechanisms underlying PM2.5 sensitivity remain unclear. We previously identified a PM2.5-sensitive asthma phenotype and developed a PM2.5 sensitivity polygenic risk score (sPRS) correlated with asthma exacerbations and lung function decline. This study expands on these results using genetic mapping and single-cell transcriptomics to elucidate the biological pathways mediating PM2.5 sensitivity and generate hypotheses regarding potential therapeutic targets. Research Question. We aimed to determine whether genetic variants associated with PM2.5 sensitivity converge on specific pathways or transcriptional regulators and assess their role in glucocorticoid responsiveness. Methods. We mapped sPRS variants to genes using regulatory annotation tools and performed pathway enrichment analysis. Single-cell RNA sequencing (scRNA-seq) was conducted on peripheral blood mononuclear cells (PBMCs) from patients stratified by sPRS and matched by PM2.5 exposure to identify transcriptional perturbations in response to PM2.5 exposure. In silico analyses predicted regulatory networks and small molecules that could modulate these pathways. Results. sPRS-associated genes were enriched for SMAD2/3 and MAPK signaling, implicating TGF-ß1 as a key mediator of PM2.5 sensitivity. scRNA-seq revealed immune cell-specific transcriptional changes linked to inflammation. Notably, HDM2 inhibition downregulated the PM2.5-sensitive transcriptomic signature, suggesting a role in restoring glucocorticoid responsiveness. Interpretation. Our findings suggest a TGF-ß1–HDM2–p53 axis may contribute to PM2.5-induced glucocorticoid resistance and identify HDM2 as a potential therapeutic target for future investigation in PM2.5-sensitive children with asthma. Overall design: This study investigates the molecular mechanisms underlying genetic susceptibility to PM2.5 exposure in pediatric asthma. We stratified children with asthma by a previously validated PM2.5 sensitivity polygenic risk score (sPRS) into high and low sPRS groups. Peripheral blood mononuclear cells (PBMCs) were collected from subjects matched for age, sex, and ambient PM2.5 exposure levels. Single-cell RNA sequencing (scRNA-seq) was performed to characterize transcriptional changes associated with sPRS status in the context of PM2.5 exposure. The experimental design aims to identify immune cell-type–specific responses, regulatory networks, and potential therapeutic targets mediating PM2.5 sensitivity.