Characterizing Metabolic Signatures of Air Pollution and Their Association With the Risk of Gout: A Population‐Based Cohort Study

Objective This study aimed to identify metabolic signatures reflecting air pollution and further explore their associations with gout risk. Methods We retrieved 207,908 gout‐free participants from a large cohort study. Annual average concentrations of fine particulate matter (PM 2.5 ), inhalable particulate matter (PM 10 ), nitrogen dioxide (NO 2 ), and nitrogen oxides (NO x ) were estimated using bilinear interpolation based on the residential address. Elastic net regression was used to identify air pollutant–related metabolites and construct metabolic signatures. Cox regression models were performed to evaluate the association between air pollutants, related metabolic signatures, and the risk of gout. Mediation analyses were performed to explore how metabolites mediate the relationships linking air pollutants to gout. Results During a median follow‐up of 12.56 years, 2,474 incident gout cases were identified. We identified metabolite biomarkers reflecting air pollutants, including 87 metabolites for PM 2.5 , 76 for PM 10 , 68 for NO 2 , and 71 for NO x . Air pollution–related metabolic signatures were associated with elevated gout risk, with hazard ratios of 1.10 (95% confidence interval [CI] 1.05–1.14) for PM 2.5 , 1.12 (95% CI 1.08–1.17) for PM 10 , 1.09 (95% CI 1.04–1.13) for NO 2 , and 1.11 (95% CI 1.06–1.15) for NO x . Consistently, per‐interquartile range increase in PM 2.5 , PM 10 , NO 2 , and NO x was associated with 17%, 15%, 6%, and 6% increased gout risk, respectively. Additionally, metabolic signatures mediated the air pollutants–gout associations, with the mediation proportions varying from 2.36% for PM 2.5 to 4.30% for NO x . Conclusion Our study indicated that air pollutants and metabolic signatures were associated with elevated gout risk, with metabolomic signatures playing a mediating role in the air pollutants–gout relationship.