Adverse exposure burden, NMR metabolomics, and risk of incident abdominal aortic aneurysm.

Background: The cumulative impact of multidomain adverse exposures on abdominal aortic aneurysm (AAA) risk and the underlying metabolic pathways remain insufficiently understood. Methods: We analyzed 304,482 UK Biobank participants free of aortic aneurysm at baseline. Twenty-six exposures were grouped into five domains to derive domain specific and overall exposure scores. Associations with incident AAA were assessed using Cox models. To explore potential metabolic pathways, we applied a two stage NMR metabolomics framework combining multivariable linear regression, metabolite specific Cox models, and a 10-fold cross validated elastic net Cox model to generate a metabolite score. Mediation analyses and XGBoost models were also performed. Results: During a mean follow up of 14.9 years, 1,671 participants developed AAA. A higher overall exposure score was associated with an increased risk of incident AAA (per SD increase: HR, 1.08; 95% CI, 1.07-1.11). Among domain specific scores, the socioeconomic, social psychology, and lifestyle scores were independently associated with AAA, whereas the environmental pollution and living environment scores were not. Current smoking showed the strongest association among individual exposures (HR, 7.95; 95% CI, 6.81-9.27). Overall exposure burden was associated with broad metabolomic perturbations, and a 13-metabolite score was significantly associated with AAA (per SD increase: HR, 1.38; 95% CI, 1.35-1.41), mediating 5.78% of this association. Adding exposure and metabolite scores improved prediction beyond clinical factors alone. Conclusions: Greater multidomain adverse exposure burden was associated with higher incident AAA risk, partly through metabolic signatures related to inflammation and lipoprotein metabolism, and may provide incremental value for AAA risk stratification.