Abstract Peripheral artery disease (PAD) is influenced by various risk factors, with environmental determinants gaining increasing attention. This study aimed to assess the impact of per- and polyfluoroalkyl substances (PFAS) on PAD using a multi-omics approach. Data from the National Health and Nutrition Examination Survey (NHANES) were analyzed to evaluate the association between PFAS exposure and PAD via generalized linear models, restricted cubic spline (RCS) functions, and subgroup analyses. Mendelian randomization (MR) analysis was conducted to explore the causal relationship between PFAS and PAD. Network toxicology was employed to identify key targets through which PFAS may contribute to PAD pathogenesis. The mediating effects of 91 inflammatory cytokines in the pathway linking core targets to PAD were also examined. After adjusting for confounders, the highest quartile of perfluorooctanoic acid (PFOA) was associated with a 635.8% increased risk of PAD compared to the lowest quartile (OR = 7.358, 95% CI: 3.378–16.029, P = 0.037). RCS analysis revealed a non-linear relationship between PFOA levels and PAD risk (P for overall = 0.001, P for nonlinear = 0.002). MR analysis further supported a causal effect of PFOA on PAD. Additionally, MMP9 was identified as a core target through which PFOA promotes PAD pathogenesis. Mediation analysis indicated that MMP9 contributes to PAD progression by increasing levels of C-C motif chemokine 28, fractalkine, and SIR2-like protein 2. These findings offer novel insights into the role of emerging organic pollutants in PAD etiology and provide valuable evidence for future preventive and therapeutic strategies.
Huang et al. (Mon,) studied this question.