Long-term Fine Particulate Matter Exposure and Coronary Artery Disease: Unraveling Cardiometabolic Pathways and Modification of Genetic Susceptibility

Abstract Aims Which cardiometabolic risk factors (CMRFs) primarily mediate the association between long-term fine particulate matter (PM2.5) exposure and coronary artery disease (CAD) incidence, and whether participants with high genetic risks of CMRFs are more susceptible remains unclear. Methods This study was based on the project of Prediction for Atherosclerotic Cardiovascular Disease Risk in China. Long-term PM2.5 concentration was assessed by satellite-based spatiotemporal model at 1km resolution. Mediation analyses were conducted to assess the mediating contribution of CMRFs for PM2.5 and CAD, and then stratified by genetic risk of CMRFs. Additive interaction was additionally evaluated on modification of genetic risk for PM2.5 and CAD. Results During a median follow-up of 11.15 years, 941 CAD cases of 34,481 participants were recorded. Each 10 μg/m3 increase in PM2.5 exposure was associated with a 28% increased risk of CAD (hazard ratio: 1.28; 95% confidence interval [CI]: 1.19, 1.37). Systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) emerged as the primary mediators, with mediating proportions of 13.02% (95%CI:4.63,21.42) and 9.23% (95%CI:0.34,18.12), respectively. Notably, individuals with high genetic risk exhibited greater mediating proportions at 18.99% (95%CI:6.43,31.55) and 16.30% (95%CI:5.11,27.52) then those with low genetic risk at 2.42% (95%CI: -16.80,21.64) and 6.15% (95%CI: -8.13,20.43). Meanwhile, the genetic risks of SBP and LDL-C also significantly exacerbated CAD risk related to PM2.5 exposure, demonstrating additive interaction (P<0.05). Conclusions This study provided a combination of conventional and genetic evidence to underscore the importance of integrated management targeting BP and blood cholesterol to mitigate CAD burden when PM2.5 exposure is unavoidable.