Annual average exposure to ambient air pollution, polygenic risk, and incidence of major chronic diseases: a large-scale prospective cohort study

Ambient air pollution is a major environmental risk factor for chronic diseases, yet its independent effects, as well as its joint associations and interactions with genetic susceptibility, on multiple chronic conditions remain understudied. This study aims to investigate the association between annual average exposure to multiple air pollutants and five major chronic diseases, while quantifying the role of polygenic risk in these relationships. We included 313,534 participants from the UK Biobank. Land use regression models were used to estimate annual average air pollution concentrations at residential addresses. Chronic diseases (cardiovascular, respiratory, neurodegenerative, hypertension, and diabetes) were identified using ICD-9 and ICD-10 codes. Weighted polygenic risk scores (PRS) were constructed for each disease. Cox proportional hazards models were used to assess associations, and additive interactions were evaluated using RERI and AP. Annual average exposure to PM2.5, PM10, NO2, and NOx was significantly associated with increased chronic disease risk. PM2.5 showed the strongest association (HR = 1.22 per 5 µg/m³, 95% CI: 1.19–1.26). High genetic risk was independently associated with disease incidence (e.g., diabetes: HR = 1.77 per SD increase in PRS). Significant additive interactions were observed between high genetic risk and high PM2.5 exposure for neurodegenerative disease (RERI = 0.14) and diabetes (RERI = 0.21). Participants with both high genetic risk and high pollution exposure had the highest disease burden. Annual average exposure to air pollutants is associated with increased risks of multiple chronic diseases, with effect modification by genetic susceptibility.