Plasma fatty acid composition modifies the cardiovascular risk of long-term PM2.5 exposure: a prospective cohort study of 428,048 participants

This study aimed to investigate whether plasma fatty acid composition is associated with incident atherosclerotic cardiovascular disease (ASCVD) and whether it modifies the cardiovascular risk associated with long-term exposure to fine particulate matter (PM 2.5 ). This prospective cohort study included 428,048 UK Biobank participants free of ASCVD at baseline. Plasma fatty acids were quantified using 1 H-NMR metabolomics, and annual residential PM 2.5 exposure was estimated using land-use regression models. Cox proportional hazards models were used to evaluate the independent associations of fatty acid indices and PM 2.5 with incident ASCVD, as well as their joint associations. Additive interaction was assessed using the relative excess risk due to interaction (RERI). During a median follow-up of 12.5 years, 45,880 incident ASCVD events were documented. Higher absolute fatty acid concentrations were positively associated with ASCVD risk, possibly reflecting underlying metabolic disturbances. In contrast, relative compositional indices, particularly the polyunsaturated-to-monounsaturated fatty acid (PUFA/MUFA) ratio and docosahexaenoic acid percentage (DHA%), were inversely associated with ASCVD risk. Compared with the lowest quartile, the highest quartile of the PUFA/MUFA ratio was associated with a 25% lower risk of ASCVD (hazard ratio [HR] = 0.75, 95% confidence interval [CI]: 0.73–0.77). A higher DHA% showed a similar inverse association. In joint analyses, significant additive interactions were observed between high PM 2.5 exposure (≥ 10 µg/m 3 ) and unfavorable fatty acid profiles. Participants with both high PM 2.5 exposure and a low PUFA/MUFA ratio had a disproportionately increased ASCVD risk (RERI = 0.08, 95% CI: 0.04–0.12; synergy index = 1.78), suggesting greater metabolic susceptibility to air pollution. A more favorable plasma fatty acid composition, characterized by a higher PUFA/MUFA ratio and higher DHA proportion, was associated with a lower risk of incident ASCVD and appeared to attenuate the excess cardiovascular risk associated with long-term PM 2.5 exposure. Improving lipid quality may represent a complementary strategy for reducing the cardiovascular burden associated with environmental air pollution.