Causal role of 731 immune cells in diabetic nephropathy: a bi-directional two-sample Mendelian randomization study.

Abstract

Background: The primary cause of end-stage renal disease (ESRD) is diabetic nephropathy (DN), and a growing body of research indicates that immunology plays a part in how DN develops into ESRD. Our objective is to identify causal relationships between various immune invading cells and DN to identify possible targets for immunotherapy.

Methods: This study used a complete Mendelian randomization (MR) analysis with two samples to identify the underlying mechanism linking immune cell characteristics with DN. Using publicly available genetic data, we investigated the causal link between 731 immune cell profiles and DN risk. Included were four different types of immune systems: morphological parameters (MP), absolute cell (AC), relative cell (RC), and median fluorescence intensities (MFI). The results' robustness, heterogeneity, and horizontal pleiotropy were confirmed through extensive sensitivity analysis.

Results: Following FDR (False Discovery Rate correction method) correction, no statistically significant differences were observed; however, six immunophenotypes were shown to be significantly associated with DN risk at the 0.25 level. Only CD28⁺ CD4^- CD8^- T cells were identified as the protective immunophenotype (OR = 0.588, 95% CI 0.437-0.792, P = 4.71 × 10^-4). Moreover, DN had no discernible impact on immunophenotyping after FDR correction. Surprisingly, three unadjusted phenotypes with low P values were discovered to be positively correlated with the risk of DN: CD20 on IgD^- CD27^- B cells (OR = 1.263, 95% CI 1.076-1.482, P = 4.22 × 10^-3), CD8 on naive CD8 + T cells with Effector Memory (OR = 1.107, 95% CI 1.013-1.209, P = 2.40 × 10^-2), and CD8 on Effector Memory CD8 + T cells (OR = 1.126, 95% CI 1.024-1.239, P = 1.46 × 10^-2).

Conclusions: Our findings provide a genetic basis for the association between immune cells and DN and should inform future clinical research.