Genetic susceptibility to PM_2.5 exposure and transcriptional responses in pediatric asthma: insights from single-cell...

Exposure to fine particulate matter (PM_2.5) increases asthma severity and reduces glucocorticoid responsiveness in children, yet the molecular mechanisms underlying PM_2.5 sensitivity remain unclear. We previously identified a PM_2.5-sensitive asthma phenotype and developed a PM_2.5 sensitivity polygenic risk score (sPRS) correlated with asthma exacerbations and lung function decline.

We sought to determine whether genetic variants contributing to PM_2.5 sensitivity converge on specific biological pathways or transcriptional regulators, and whether children with a high sPRS exhibit immune transcriptional signatures consistent with heightened PM_2.5 susceptibility.

Genes implicated by sPRS variants were mapped using regulatory annotation tools and evaluated for pathway and transcription factor target enrichment. Peripheral blood mononuclear cells (PBMCs) from high- and low-sPRS children matched on long-term ambient PM_2.5 exposure were profiled using single-cell RNA sequencing. Donor-level pseudobulk differential expression was performed using a paired quasi-likelihood negative binomial framework, followed by exploratory pathway enrichment and perturbagen signature analyses.

sPRS-implicated genes were enriched for transcriptional regulators linked to SMAD2/3- and MAPK-associated signaling, suggesting TGF-β1-related pathway involvement. No genes reached false-discovery-rate-adjusted significance at the donor level in this small, matched cohort. However, secondary pathway-level analyses demonstrated concordant enrichment across multiple immune populations in inflammatory and stress-response signaling programs previously linked to PM_2.5 exposure. Perturbagen signature analyses likewise highlighted small-molecule regulators of TGF-β1-associated pathways.

These integrative genomic and transcriptomic analyses nominate TGF-β1-SMAD/MAPK signaling as a biologically plausible axis of genetic susceptibility to PM_2.5 in pediatric asthma. Given the modest sample size and indirect nature of enrichment-based inference, these findings should be considered hypothesis-generating and motivate targeted functional validation.