Understanding the biological mechanisms linking long-term ambient air pollution to cardiovascular disease (CVD) is crucial for effective prevention, as air pollution remains a leading environmental determinant of CVD worldwide. The serum metabolome-reflecting integrated biochemical responses to environmental and genetic influences-offers a unique window into systemic perturbations induced by pollution exposure.
This project aims to elucidate how long-term exposure to ambient air pollutants alters circulating metabolites and to determine whether these metabolomic changes mediate subsequent CVD risk. Key unresolved questions include: (1) which serum metabolites or metabolic pathways are associated with chronic air pollution exposure; (2) whether these pollution-related metabolic signatures predict incident CVD or its subtypes; and (3) how demographic, metabolic, or genetic factors modify these associations.
We hypothesize that long-term air pollution induces pollutant-specific metabolic perturbations that partially mediate its impact on CVD, with the magnitude of mediation varying across demographic and genetic strata. Leveraging the UK Biobank’s extensive cohort-with detailed NMR-based metabolomics, high-resolution pollution exposure models, genomic data, and long-term CVD follow-up-this study will integrate environmental, molecular, and genetic data to uncover causal pathways.
Specifically, we will (1) identify serum metabolites associated with long-term exposure to key pollutants; (2) estimate the indirect effects of air pollution on CVD via metabolomic intermediates using causal mediation analysis; and (3) assess effect modification by age, sex, metabolic status, and polygenic risk. Findings will provide mechanistic insight into pollution-induced cardiometabolic disruption and inform precision public health interventions targeting high-risk populations.
