Perfluorooctane Sulfonate Exposure and Peripheral Artery Disease: Mendelian Randomization and Integrative Multi-Omics...

Area of Science:

• Environmental Health
• Cardiovascular Epidemiology
• Toxicology

Background:

• Observational studies suggest links between per- and polyfluoroalkyl substances (PFAS) and cardiovascular disease, but causal evidence is limited.
• Confounding, measurement error, and reverse causation are challenges in existing epidemiological research on PFAS and cardiovascular outcomes.

Purpose of the Study:

• To investigate potential causal associations between perfluorooctanoic acid (PFOA) or perfluorooctanesulfonic acid (PFOS) exposure and five cardiovascular diseases using Mendelian randomization.
• To identify molecular targets and pathways involved in PFOS-related cardiovascular effects through network toxicology and machine learning.
• To explore immune mechanisms and pollutant-protein interactions in peripheral artery disease (PAD).

Main Methods:

• Two-sample Mendelian randomization analysis utilizing European-ancestry GWAS data.
• Integration of network toxicology with transcriptomic data for candidate target identification.
• Machine learning, immune cell infiltration analysis, single-cell transcriptomics, molecular docking, and molecular dynamics simulations.

Main Results:

• Genetically predicted PFOS exposure was associated with an increased risk of peripheral artery disease (PAD).
• Enrichment analysis implicated PPAR and PI3K-Akt signaling pathways.
• Machine learning identified HMOX1, KDR, MMP9, and PPARG as key targets; PFOS-HMOX1 binding was supported by simulations.

Conclusions:

• Findings suggest a potential causal association between PFOS exposure and PAD.
• The study provides candidate biomarkers (HMOX1, KDR, MMP9, PPARG) for further investigation.
• Immune microenvironment remodeling in PAD and specific pollutant-protein interactions were elucidated.