Deciphering genetic susceptibility to diabetic neuropathy: immune cell causality revealed

Aims: The study aimed at evaluating 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 used as the main tool for MR analysis. Horizontal pleiotropy, heterogeneity, and robustness of the MR results were assessed 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).

Conclusions: This MR analysis identified seven immune cell phenotypes associated with increased genetic susceptibility to DN. These preliminary results should be validated through further experimental studies in different populations.

Comments. The reason for bringing this study up is because traditional models related to pathophysiology/progression of DN have been exclusively related to metabolic criteria e.g. HbA1c, triglycerides, hypertension, smoking etc. This study introduces the provoking concept of genetic susceptibility to DN in addition to metabolic milieu. All of us have seen subjects with long-standing diabetes (Type 1 or 2) who do not have any DN despite years of suboptimal control – is this related to a genetic linkage affecting resistance to the risk factors? Although this data was obtained only from the European Bioinformatics Institute and FinnGen, it remains to be seen if the same MR analysis applies to other ethnicities. Similarly, AI learnings from UK Biobank (Allwright M et al Diabetes Res Clin Pract. 2023;201:110725) suggest risk factors for DN include CRP and Cystatin-C while the involvement of immune cells, such as neutrophils and monocytes, is sex specific.

Sanjeev Sharma

Reference. Yu Y, Yang X, Yin Y, Deng J, Chen C, Yu R. Deciphering diabetic neuropathy: immune cell causality revealed. Neurol Res. 2025 Sep;47(9):782-790.

🔗 https://www.tandfonline.com/doi/10.1080/01616412.2025.2503456?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed