Abstract
BACKGROUND: Diabetic nephropathy (DN) stands as a pervasive chronic renal disease worldwide, emerging as the leading cause of renal failure in end-stage renal disease. Our objective is to pinpoint potential immune biomarkers and evaluate the causal effects of prospective therapeutic targets in the context of DN. METHODS: We employed Mendelian randomization (MR) analysis to examine the causal associations between 731 immune cell signatures and the risk of DN. Various analytical methods, including inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode, were employed for the analysis. The primary analytical approach utilized was the inverse-variance weighted (IVW) method. To ensure the reliability of our findings, we conducted comprehensive sensitivity analyses to assess the robustness, heterogeneity, and presence of horizontal pleiotropy in the results. Statistical powers were also calculated. Ultimately, a reverse Mendelian randomization (MR) analysis was conducted to assess the potential for reverse causation. RESULTS: After Benjamini & Hochberg (BH) correction, four immunophenotypes were identified to be significantly associated with DN risk: HLA DR on Dendritic Cell (OR=1.4460, 95% CI = 1.2904~1.6205, P=2.18×10(-10), P.adjusted= 1.6×10(-7)), HLA DR on CD14(+) CD16(-) monocyte (OR=1.2396, 95% CI=1.1315~1.3580, P=3.93×10(-6), P.adjusted = 0.00143). HLA DR on CD14(+) monocyte (OR=1.2411, 95% CI=1.12957~1.3637, P=6.97×10(-6), P.adjusted=0.0016), HLA DR on plasmacytoid Dendritic Cell (OR=1.2733, 95% CI= 1.1273~1.4382, P= 0.0001, P.adjusted = 0.0183). Significant heterogeneity of instrumental variables was found in the four exposures, and significant horizontal pleiotropy was only found in HLA DR on Dendritic Cell. The bidirectional effects between the immune cells and DN were not supported. CONCLUSION: Our research illustrated the intimate association between immune cells and DN, which may contribute to a deeper understanding of the intricate mechanisms underlying DN and aid in the identification of novel intervention target pathways.