Immunoproteomic mediators of diabetic peripheral neuropathy: causal insights from Mendelian randomization and single-cell validation

Objective: To elucidate causal roles of circulating immune cells and plasma proteins in diabetic peripheral neuropathy (DPN) pathogenesis using integrative Mendelian randomization (MR) and single-cell validation. Methods: We employed two-sample MR to assess causal effects of 731 immune traits and 4,719/2,923 plasma proteins on DPN risk (FinnGen: 2,843 cases/389,580 controls). Significant exposures underwent mediation MR to identify protein-immune interactions. Validation included scRNA-seq of sural nerves (4 DPN vs. 3 controls) and flow cytometry/immunofluorescence for dendritic cell infiltration. Results: immune phenotypes (predominantly dendritic subsets) increased DPN risk (OR = 1.27-1.63, FDR