Plasma Proteins and Genes Associated with Protein and Risks for Diabetic Foot Diseases Identified Using Multi- Ornics and Mendelian Randomization Analysis.

INTRODUCTION: Diabetic foot diseases (DFD) severely impair quality of life, yet specific biomarkers and effective therapies remain limited. Identifying causal molecular targets is critical to address this unmet need.

METHODS: We integrated plasma proteome and genome-wide data with Mendelian randomization (MR) to screen therapeutic targets for DFD. Genetic instruments (pQTLs/e- QTLs) proxied plasma protein and gene expression levels. Causal effects on three DFD outcomes (peripheral atherosclerosis, neuropathy, charcot foot) were analyzed via inverse variance weighting and summary-data-based MR. Functional enrichment and colocalization analyses elucidated biological pathways and shared genetic variants.

RESULTS: MR identified three protective plasma proteins(EPOR, MICA, and PRKCG), significantly reducing risks across all DFD outcomes, and one risk plasma protein TXNDC15. SMR revealed 42 blood-expressed genes that show significant causal effects on all the DM-related traits. These targets were enriched in immune-inflammatory pathways (e.g., staphylococcal infection, NF-κB signaling). Colocalization confirmed shared causal variants between CEP68/FLOT1 and DFD outcomes (posterior probability > 0.87).

DISCUSSION: Our study establishes a novel theoretical framework for DFD mechanisms through multi-omics and MR integration, highlighting its significant research value, though further experimental validation is needed. These findings bridge the gap between causal genetic insights and precision medicine strategies for DFD management.

CONCLUSION: This multi-omics MR study prioritizes EPOR, PRKCG, MICA, and TXNDC15 plasma proteins, 42 plasma genes as causal contributors to DFD, offering mechanistic insights and novel targets for therapeutic development.