Deciphering diabetic neuropathy: immune cell causality revealed.

Objective: This study assessed the causal effects of immune cell phenotypes on diabetic neuropathy (DN) using Mendelian randomization (MR) analysis.

Methods: Datasets of immune cell phenotypes and DN were collected from the European Bioinformatics Institute and FinnGen. Single nucleotide polymorphisms that met the specified criteria were subjected to a stepwise selection based on the hypotheses of association, independence, and exclusivity. Inverse variance weighted was employed as the main tool for MR analysis. Horizontal pleiotropy, heterogeneity, and robustness of the MR results were evaluated using the MR-Egger intercept, Cochran's Q, and leave-one-out sensitivity analyses, respectively.

Results: MR analysis revealed that CD24+CD27+ %lymphocyte (odds ratio [OR]: 1.043, 95% confidence interval [CI]: 1.007‒1.080, p = 0.018, false discovery rate [FDR] = 0.998), CD24+CD27+ AC (OR: 1.041, 95% CI: 1.004‒1.079, p = 0.030, FDR = 0.998), CD28-CD127-CD25++CD8br %T cell (OR: 1.069, 95% CI: 1.003‒1.140, p = 0.042, FDR = 0.998), CD28-CD25++CD8br AC (OR: 1.095, 95% CI: 1.019‒1.177, p = 0.014, FDR = 0.998), CD33-HLA DR - AC (OR: 1.079, 95% CI: 1.007‒1.156, p = 0.031, FDR = 0.998), CD8 on CM CD8br (OR: 1.135, 95% CI: 1.012‒1.273, p = 0.030, FDR = 0.998), and naïve CD4+ %CD4+ (OR: 1.119, 95% CI: 1.030‒1.215, p = 0.008, FDR = 0.787) were associated with increased genetic susceptibility to DN. The MR-Egger intercept analysis indicated the absence of horizontal pleiotropy (p ≥ 0.05) and Cochran's Q test showed that the results were not heterogeneous (p ≥ 0.05).

Conclusion: This MR analysis revealed seven immune cell phenotypes associated with increased genetic susceptibility to DN. These findings are preliminary and warrant further experimental validation in different populations to confirm their significance.