Table4_Causal role of immune cells in diabetic nephropathy: a bidirectional Mendelian randomization study.xlsx

BackgroundDiabetic 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.
MethodsWe 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.
ResultsAfter 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.
ConclusionOur 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.

背景：糖尿病肾病（Diabetic nephropathy, DN）是全球范围内流行的慢性肾脏疾病，亦是终末期肾病中肾衰竭的首要诱因。本研究旨在明确潜在的免疫生物标志物，并评估潜在治疗靶点在糖尿病肾病情境下的因果效应。
方法：我们采用孟德尔随机化（Mendelian randomization, MR）分析，探究731种免疫细胞特征与糖尿病肾病发病风险之间的因果关联。分析过程中采用了多种统计学方法，包括逆方差加权（inverse-variance weighted, IVW）、MR-Egger、加权中位数法、简单众数法以及加权众数法，其中以逆方差加权法作为主要分析手段。为确保研究结果的可靠性，我们开展了全面的敏感性分析，以评估结果的稳健性、异质性及横向多效性是否存在，并计算了统计效力。最终，我们还实施了反向孟德尔随机化（reverse Mendelian randomization, MR）分析，以排查反向因果关联的可能性。
结果：经Benjamini & Hochberg（BH）校正后，共筛选出4种与糖尿病肾病风险显著相关的免疫表型：树突状细胞表面HLA DR（比值比（odds ratio, OR）=1.4460，95%置信区间（confidence interval, CI）=1.2904~1.6205，P=2.18×10−10，校正后P值P.adjusted=1.6×10−7）、CD14+ CD16−单核细胞表面HLA DR（OR=1.2396，95%CI=1.1315~1.3580，P=3.93×10−6，P.adjusted=0.00143）、CD14+单核细胞表面HLA DR（OR=1.2411，95%CI=1.12957~1.3637，P=6.97×10−6，P.adjusted=0.0016）以及浆细胞样树突状细胞表面HLA DR（OR=1.2733，95%CI=1.1273~1.4382，P=0.0001，P.adjusted=0.0183）。上述4种暴露因素的工具变量均存在显著异质性，且仅在树突状细胞表面HLA DR中检测到显著的横向多效性。未发现免疫细胞与糖尿病肾病之间存在双向因果关联。
结论：本研究揭示了免疫细胞与糖尿病肾病之间的紧密关联，这将有助于加深对糖尿病肾病复杂发病机制的理解，并为识别新型干预靶点通路提供理论依据。