Immune cell phenotypes in the context of diabetic nephropathy: A Mendelian randomization analysis

To clarify whether specific immune cell phenotypes exert a causal influence on diabetic nephropathy (DN), we conducted a Mendelian randomization (MR) investigation using large-scale genetic datasets. Summary-level data for immune cell traits and DN were obtained from recent genome-wide association studies and the FinnGen consortium. Genetic instruments were selected under the core MR assumptions, ensuring strong relevance and minimal confounding. The inverse-variance weighted approach served as the primary analytical framework. Complementary analyses, including MR-Egger regression, Cochran Q test, and leave-one-out procedures, were performed to detect horizontal pleiotropy, assess heterogeneity, and evaluate the stability of the findings. Genetically predicted increases in several immune cell phenotypes were associated with higher genetic susceptibility to DN, including CD25 on IgD- CD38dim (odds ratio [OR]: 1.153, P = .026), CD8dim AC (OR: 1.144, P = .045), HLA DR on CD33br HLA DR+ CD14- (OR: 1.142, P < .001), CD39+ CD8br %CD8br (OR: 1.094, P = .047), and CD25hi CD45RA+ CD4 not Treg %T cell (OR: 1.051, P = .041). Conversely, higher SSC-A on CD4+ cells was associated with lower genetic susceptibility to DN (OR: 0.385, P < .001). No evidence of horizontal pleiotropy was detected (P ≥ .05). Cochran Q indicated no significant heterogeneity. Sensitivity analyses confirmed the robustness of all associations. This MR analysis suggests that HLA DR on CD33br HLA DR+ CD14- is associated with increased genetic susceptibility to DN, whereas SSC-A on CD4+ is associated with decreased susceptibility. These findings offer genetic evidence of immune involvement in DN susceptibility and warrant further validation and investigation to clarify mechanisms and relevance.