Abstract
While air pollution is a recognized cardiovascular risk, its specific impact on aortic stenosis (AS) remains poorly characterized. This study investigates the association between air pollution and incident AS, integrating gene-environment interactions and network toxicology. Based on the UK Biobank as the primary cohort, long-term air pollution exposure (per standard deviation increase) is associated with an increased risk of AS, with HRs and 95% CIs of 1.60 (1.55,1.66) for PM2.5, 1.37 (1.32, 1.41) for PM10, 1.37 (1.32, 1.42) for NO2, and 1.36 (1.31, 1.41) for NOx. The observed associations demonstrate high consistency across a suite of advanced internal methodological validations and are further replicated in the Tianshan Community Cohort. There are joint and interactive effects of genetic susceptibility and air pollutants on AS risk. Network toxicology and bioinformatics analyses reveal key PM-AS target genes enriched in the lipid and atherosclerosis, fluid shear stress and atherosclerosis, and IL-17 signaling pathway. In conclusion, long-term exposure to PM2.5, PM10, NO2, and NOx is significantly associated with an increased AS risk, with a potential interaction between environmental exposure and genetic susceptibility.