Plasma metabolite octadecadienedioate: A novel protective factor against diabetes-related Charcot foot.

Charcot foot (CF) is a severe, progressive neuro-osteoarthropathy predominantly affecting diabetic patients with peripheral neuropathy. Characterized by progressive bone and joint destruction, CF can lead to debilitating foot deformities, ulceration, infection, and ultimately lower extremity amputation. Despite its significant clinical impact, the global prevalence remains uncertain, with an estimated 1.6 million people affected worldwide. Early diagnosis is challenging due to the insidious onset and limited specificity of current clinical, imaging, and laboratory assessments. The role of circulating metabolites in CF pathogenesis remains poorly understood. This study aimed to investigate the causal relationship between plasma metabolites and CF risk using Mendelian randomization (MR) and to identify potential biomarkers for early detection and therapeutic intervention. We conducted a bidirectional 2-sample MR study using genome-wide association study summary data. Plasma metabolite data were obtained from a cohort of approximately 8000 individuals of European descent (genome-wide association study catalog: GCST90199621-GCST90201020), and CF summary statistics were derived from the FinnGen Study (9th version), comprising 473 cases and 271,817 controls. Genetic instrumental variables were selected through linkage disequilibrium clumping and harmonization. The inverse-variance weighted method served as the primary analysis, supplemented by MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses included Cochran Q test, Egger intercept test, MR-Pleiotropy RESidual Sum and Outlier, and leave-one-out analyses. Multivariable MR and colocalization analyses were performed to validate the findings. After false discovery rate adjustment, octadecadienedioate demonstrated a significant negative association with CF risk (odds ratio = 0.644, 95% confidence interval 0.528-0.785, false discovery rate = 0.018). This protective association was consistent across all MR methods, robust in sensitivity analyses, and further supported by multivariable MR (odds ratio = 0.632, 95% confidence interval 0.479-0.834) and colocalization analysis (posterior probability 4 = 0.945). Reverse MR analysis revealed no significant causal effects from CF to metabolite levels. Our findings identify octadecadienedioate as a novel protective factor against CF, highlighting the potential of circulating metabolites in understanding CF pathogenesis. These results may inform future preventive strategies, biomarker development, and personalized diabetic foot care.