Exploring the causal relationship between inflammatory cytokines and diabetic foot ulcer: A bidirectional Mendelian randomization and clinical validation study

Diabetic foot ulcers (DFU) are a major complication of diabetes, often driven by chronic inflammation. The role of specific inflammatory cytokines in DFU development is unclear due to challenges in observational studies. This study used a two-sample, bidirectional Mendelian randomization (MR) approach to assess the causal effects of 41 circulating inflammatory cytokines on DFU risk. Instrumental variables were selected based on genome-wide significance and linkage disequilibrium criteria. The primary analysis was inverse-variance weighted (IVW), with validation through enzyme-linked immunosorbent assay (ELISA) and real-time PCR (RT-PCR) in DFU patients and controls. Genetically predicted levels of CTACK (CCL27) and MIG (CXCL9) were linked to reduced DFU risk, with odds ratios of 0.538 for CTACK and 0.501 for MIG. Sensitivity analyses confirmed the robustness of the findings. Reverse MR analysis showed no causal relationship between DFU and these cytokines. Clinical validation revealed lower protein and mRNA levels of CTACK and MIG in DFU patients. This study provides evidence for a protective role of CTACK and MIG in DFU development, suggesting they could serve as biomarkers or therapeutic targets for diabetic wound care.