Identification of shared and divergent molecular pathways linking ambient air pollutants to mortality and major chronic diseases through proteomic profiling.

Ambient air pollutants have been associated with increased risks of mortality and chronic diseases; however, population-based evidence on their shared versus pollutant- and outcome-specific molecular mechanisms remains unclear. Leveraging proteomics data from 48,645 participants in the UK Biobank, we characterized proteomic signatures related to overall and individual air pollutants, including particulate matter (PM2.5 and PM10), nitrogen dioxide (NO2) and nitrogen oxides (NOx), and examined their associations with risks of mortality and major chronic diseases. Subsequently, we investigated potential mediating proteins underlying these associations to determine relevant biological mechanisms through functional annotation analyses. Plasma proteins jointly associated with four air pollutants were commonly enriched in immune regulatory pathways, while proteins uniquely associated with PM2.5, PM10, NO2, and NOx were enriched in pollutant-specific pathways of vascular dysfunction, DNA damage, apoptosis signaling, and extracellular matrix remodeling, respectively. Proteomic signatures of air pollutants captured biological processes underlying mortality and major chronic diseases. Mediation analyses and Mendelian randomization identified mediating proteins causally associated with their respective health outcomes, highlighting shared mechanisms of inflammation and immune response as well as outcome-specific pathways such as vascular remodeling for cardiovascular disease, oxidative stress for chronic kidney disease, and cell adhesion for dementia. Specifically, cell-type and tissue enrichment annotation revealed outcome-relevant specificity of advanced glycosylation end product-specific receptor (AGER) for chronic respiratory disease and lung cancer. This study dissects the relationship between ambient air pollutants and adverse health outcomes by revealing both shared and divergent mechanisms and representing potential targets such as AGER for disease prevention and therapeutic intervention.