Air Pollution and Incident Cardiovascular Disease: Modification by Genetic Susceptibility and the Mitigating Role of Physical Activity

Background The interplay and joint effects of air pollution, genetic predisposition, and physical activity (PA) on incident cardiovascular disease (CVD) remain poorly understood. This study aimed to examine the associations between various air pollutants and CVD and assessed potential modification by genetic susceptibility and PA. Methods This prospective cohort study included 330 481 UK Biobank participants without baseline CVD. Annual average concentrations of particulate matter <2.5 μm (PM 2.5 ), PM 10 , PM 2.5–10 , nitrogen oxides, and nitrogen dioxide were estimated using land‐use regression models. Cox proportional hazards models were exploited to estimate hazard ratio (HR) and 95% CI for CVD associated with air pollution. Multiplicative and additive interactions between air pollution, genetic risk, and PA were assessed. Results During a median follow‐up of 11.8 years, 45 565 incident CVD events occurred. Individual pollutants and a composite air pollution score were positively associated with CVD. Each 5 mg/m 3 increase in PM 2.5 (HR, 1.118 [95% CI, 1.070–1.169]), PM 10 (HR, 1.090 [95% CI, 1.063–1.118]), nitrogen oxides (HR, 1.009 [95% CI, 1.006–1.012]), or nitrogen dioxide (HR, 1.027 [95% CI, 1.022–1.033]) was linked to higher CVD risk. Participants jointly exposed to high air pollution and high genetic risk had the highest CVD incidence (HR, 1.666 [95% CI, 1.590–1.746]) ( P interaction <0.001), whereas moderate or vigorous PA was protective mainly among those with low pollution and low genetic risk. Conclusions Long‐term exposure to ambient air pollutants was associated with higher CVD risk, particularly among those with high genetic susceptibility. Although PA was protective overall, its benefit was attenuated under higher air‐pollution and genetic burdens, underscoring the importance of integrating environmental control with individualized prevention strategies.