Independent and joint effect of genetic susceptibility and long-term PM2.5 exposure on coronary artery disease risk: A large-scale cohort study

Background Long-term exposure to fine particulate matter ≤ 2.5 μm (PM 2.5 ) is a major cardiovascular risk factor, yet its interaction with genetic susceptibility in coronary artery disease (CAD) remains uncertain. We investigated the independent and joint effects of PM 2.5 and polygenic risk on incident CAD. Methods A genome-wide polygenic risk score (PRS) was derived using a five-fold cross-validation framework in a large Taiwanese hospital-based cohort (n = 351,661). In the primary analysis, 148,735 adults were followed to estimate the association between long-term PM 2.5 , assessed using a validated 1-km spatiotemporal model, and incident CAD. Gene–environment interactions were assessed in a subset of 60,017 participants with available genotyping data using Cox proportional hazards models. Results Over a median follow-up of 4.6 years, 11,127 CAD events were recorded. Each 10-μg/m 3 increase in PM 2.5 exposure was associated with a 14% higher hazard of incident CAD (hazard ratio [HR]: 1.14, 95% CI: 1.08–1.20), and each standard deviation increase in PRS was associated with a 7% higher hazard of incident CAD (HR: 1.07, 95% CI: 1.05–1.10). In joint analyses, PM 2.5 exposure and genetic susceptibility each independently contributed to CAD hazard without significant interaction, with the highest hazard observed among individuals with both high PRS and high PM 2.5 exposure (HR: 1.24, 95% CI: 1.14–1.36). Conclusions Long-term PM 2.5 exposure and polygenic susceptibility each independently contributed to the hazard of incident CAD, and individuals with both high genetic risk and high PM 2.5 exposure had the highest observed hazard. These findings suggest that environmental exposure reduction and genetic risk identification may serve as complementary approaches to CAD prevention, particularly in populations with substantial air pollution burden.