The effects of circulating proteins and metabolites on diabetic foot ulcer: A Mendelian randomization study and mediation analysis.

Diabetic foot ulcers (DFUs) are a common and severe complication of diabetes, and understanding the biological mechanisms underlying their development is crucial for identifying potential biomarkers and therapeutic targets. Recent advances in Mendelian randomization (MR) and mediation analysis have provided new ways to explore the causal relationships between circulating proteins, metabolites, and diseases. This study aims to investigate the causal relationships between circulating proteins, metabolites, and DFU using MR and mediation analysis, leveraging publicly available genome-wide association studies datasets. We applied a bi-directional 2-sample MR approach to analyze 2923 circulating proteins, 1400 metabolites, and DFU, with single nucleotide polymorphisms as instrumental variables. Mediation analysis was used to explore potential causal pathways between proteins, metabolites, and DFU. Our analysis identified 42 circulating proteins and 50 metabolites with significant unidirectional causal effects on DFU. Notably, specific proteins influenced metabolites that may, in turn, contribute to DFU development. Mediation analysis revealed a causal chain where the protein GLB1 exerts an effect on DFU through the metabolite 2-linoleoylglycerol (18:2), with a mediation ratio of 10.91%. Sensitivity analyses confirmed the robustness of our findings, with no significant bias from heterogeneity or pleiotropy. These results highlight the complex interactions between proteins, metabolites, and DFU. Our findings suggest that circulating proteins may influence DFU through specific metabolites, providing valuable insights into potential biomarkers and therapeutic targets for DFU. This study demonstrates the utility of MR and mediation analysis in understanding the biological mechanisms underlying complex diseases like DFU.