Exploring the role of immune cell traits and circulating inflammatory cytokines in the development of diabetic neuropathy.

BACKGROUND

Complex interactions of metabolic abnormalities, immune cell activation, and chronic inflammation are considered critical factors in the pathogenesis and progression of diabetic neuropathy (DN). However, the association between circulating inflammatory cytokines, immune cell traits, and DN remains unclear.

METHODS

We utilized summary data from genome-wide association studies to assess the causal relationship between 731 kinds of circulating immune cell traits, 91 types of circulating inflammatory factors, and the risk of DN development via Mendelian randomization (MR) analysis. The inverse variance weighted (IVW) method was considered the primary analysis method. In addition, a series of sensitivity analyses were conducted to assess the robustness of the results.

RESULTS

The study included 3862 patients with DN and 92,612 controls from FinnGen. After false discovery rate (FDR) correction, there were two circulating immune cell traits showed significantly positive associations with DN, including higher median fluorescence intensities (MFI) of HLA DR on plasmacytoid DC and HLA DR on DC (OR = 1.21; 95 % CI: 1.10-1.31, P < 0.001, PFDR < 0.01 and OR = 1.27; 95 % CI: 1.15-1.40, P < 0.001, PFDR < 0.01, respectively). In addition, although no circulating inflammatory factors remained statistically significant after FDR correction, three cytokines showed nominal associations. Interleukin-17 A (IL-17 A) levels (OR = 1.25; 95 % CI: 1.07-1.46, P = 0.004, PFDR = 0.19) were associated with an increased risk, whereas tumor necrosis factor ligand superfamily member 14 (TNFSF14) levels (OR = 0.84; 95 % CI: 0.75-0.94, P = 0.001, PFDR = 0.15) and hepatocyte growth factor (HGF) levels (OR = 0.80; 95 % CI: 0.69-0.93, P = 0.004, PFDR = 0.13) exhibited potential protective effects. Sensitivity analyses did not detect any outliers that would significantly influence the results.

CONCLUSIONS

This study focused on the causal relationships between circulating inflammatory cytokines, immune cell characteristics, and DN, offering novel perspectives for exploring the underlying biological mechanisms of DN and holding promise for its early diagnosis, treatment, and prevention. However, these findings still require further validation through high-quality, evidence-based research to confirm their specific clinical implications.