Causal relationship between 731 immune cells and the risk of diabetic nephropathy: a two‑sample bidirectional Mendelian randomization study

Previous observational studies have indicated associations between various immune cells and diabetic nephropathy (DN). However, the causality remains unclear. We aimed to further evaluate the causal association between immune cells and DN using bidirectional two-sample Mendelian randomization (MR) analysis. The DN data were retrieved from the IEU OpenGWAS Project database, while the data for 731 immune cells were sourced from GWAS summary statistics by Orru ̀ et al. The investigation into the causal relationship between immune cells and DN employed the inverse variance weighted (IVW), weighted median (WME), and MR-Egger methods. The stability and reliability of the findings underwent evaluation through Cochran’s Q test, MR-Egger intercept’s <i>P</i>-value, MR-PRESSO, and Leave-One-Out (LOO) method. The IVW estimates suggested a positive causal effect of CD25 on IgD-CD38dim B cell, CD25 on naive-mature B cell, CD127 on granulocyte, SSC-A on HLA DR + Natural Killer, HLA DR on plasmacytoid Dendritic Cell, and HLA DR on Dendritic Cell on DN. Conversely, the abundance of Myeloid Dendritic Cell, CD62L- Dendritic Cell �ndritic Cell, CD86+ myeloid Dendritic Cell �ndritic Cell, CD14- CD16-, CX3CR1 on CD14- CD16-, and SSC-A on CD4+ T cell had negative causal effects on DN. However, after correcting the <i>P</i> value for significant causality results using the FDR method, it was concluded that only Myeloid Dendritic Cells had a causal relationship with DN (FDR-<i>p</i> = 0.041), while the other immune cells showed no significant association with DN, so their relationship was suggestive. The results were stable with no observed horizontal pleiotropy and heterogeneity. Reverse MR analysis indicated no causal relationship between DN and the increased risk of positively identified immune cells. This study provides an initial insight into the genetic perspective of the causal relationship between immune cells and DN. It establishes a crucial theoretical foundation for future endeavors in precision medicine and individualized treatment.

既往观察性研究已揭示多种免疫细胞与糖尿病肾病（diabetic nephropathy, DN）存在关联，但二者的因果关系尚未明确。本研究旨在通过双向两样本孟德尔随机化（bidirectional two-sample Mendelian randomization, MR）分析，进一步评估免疫细胞与糖尿病肾病之间的因果关联。
糖尿病肾病数据取自IEU开放全基因组关联研究（Genome-Wide Association Study, GWAS）项目数据库，731种免疫细胞的数据来源于Orru等人发布的GWAS汇总统计量。本研究采用逆方差加权（inverse variance weighted, IVW）、加权中位数（weighted median, WME）及MR-Egger三种方法，探究免疫细胞与糖尿病肾病的因果关系。
通过科克兰Q检验（Cochran’s Q test）、MR-Egger截距P值、MR-PRESSO及留一法（Leave-One-Out, LOO）对研究结果的稳定性与可靠性进行评估。
逆方差加权分析结果显示，CD25对IgD-CD38dim B细胞、CD25对幼稚成熟B细胞、CD127对粒细胞、SSC-A对HLA DR+自然杀伤细胞、HLA DR对浆细胞样树突状细胞以及HLA DR对树突状细胞存在正向因果效应，可影响糖尿病肾病的发生风险。
反之，髓系树突状细胞、CD62L-树突状细胞、CD86+髓系树突状细胞、CD14-CD16-细胞、CX3CR1对CD14-CD16-细胞以及SSC-A对CD4+T细胞的丰度对糖尿病肾病存在负向因果效应。
然而，采用错误发现率（False Discovery Rate, FDR）方法对显著因果关联结果进行P值校正后发现，仅髓系树突状细胞与糖尿病肾病存在因果关联（FDR-p=0.041），其余免疫细胞与糖尿病肾病的关联仅具有提示性意义。
本研究结果稳定性良好，未观察到水平多效性（horizontal pleiotropy）与异质性（heterogeneity）。反向孟德尔随机化分析显示，糖尿病肾病与此前鉴定出的免疫细胞丰度升高之间不存在因果关系。
本研究从遗传学视角初步揭示了免疫细胞与糖尿病肾病之间的因果关联，为未来精准医学与个体化治疗的相关研究奠定了重要的理论基础。