The causal effect of inflammatory proteins and immune cell populations on diabetic nephropathy: evidence from Mendelian randomization.

Diabetic nephropathy (DN) is one of the diabetic microvascular complications with complex pathophysiology, and exploring the landscape of immune dysregulation in DN is valuable for pathogenesis and disease treatment. We crystallized possible inflammatory exposures into 91 circulating inflammatory proteins and 109 blood immune cells; and assessed the causal relationship between inflammation and DN using Mendelian randomization (MR). Based on publicly available genetic data, we explored causal associations between inflammation and DN risk by two-sample MR analysis. Genome-wide association study (GWAS) summary statistics for 91 circulating inflammatory proteins, 109 immune cells absolute counts, and DN were acquired from the GWAS Catalog. Inverse Variance Weighted (IVW) was the main MR method, while MR-Egger and MR-pleiotropy residuals and outliers (MR-PRESSO) were utilized for sensitivity analysis. Cochrane's Q was used to test for heterogeneity. The leave-one-out method ensured the stability of the MR results. This study revealed that higher levels of TNF-related activation-induced cytokine and tumor necrosis factor ligand superfamily member 14 were possibly associated with the increased risk of DN according to the IVW approach, with estimated odds ratios (OR) of 1.287 (95% confidence interval [CI] 1.051 to 1.577, P = 0.015) and 1.249 (95% CI 1.018 to 1.532, P = 0.033). Five immune cell traits were identified that might be linked to increased DN risk, including the higher absolute counts of HLA DR+ natural killer cell (OR = 1.248, 95% CI 1.055 to 1.476, P = 0.010), IgD+ CD38+ B cell (OR = 1.148, 95% CI 1.033 to 1.276, P = 0.010), CD25++ CD8+ T cell (OR = 1.159, 95% CI 1.032 to 1.302, P = 0.013), CD4- CD8- T cell (OR = 1.226, 95% CI 1.032 to 1.457, P = 0.020), and IgD- CD38- B cell (OR = 1.182, 95% CI 1.009 to 1.386, P = 0.039). In addition, elevated levels of interleukin-1 alpha (OR = 0.712, 95% CI 0.514 to 0.984, P = 0.040) and unswitched memory B cell (OR = 0.797, 95% CI 0.651 to 0.974, P = 0.027) may reduce the risk of developing DN. We identified inflammation-related exposures that may be associated with the risk of DN at the level of genetic prediction, which contributes to a better understanding of the etiologic of DN and facilitates the development of targeted therapies for DN.

Ren Y ，Zhang H 《-》

A Mendelian randomization study investigating the causal relationships between inflammation and immunoglobulin A nephropathy.

Immunoglobulin A nephropathy (IgAN) is an autoimmune disease characterized by the production of galactose‑deficient IgA1 (Gd‑IgA1) and the deposition of immune complexes in the kidney. Exploring the landscape of immune dysregulation in IgAN is valuable for pathogenesis and disease treatment. We conducted Mendelian randomization (MR) to assess the causal correlations between inflammation and IgAN. Based on available genetic datasets, we investigated potential causal links between inflammation and the risk of IgAN using two-sample MR. We used genome-wide association study (GWAS) summary statistics of 5 typical inflammation markers, 41 inflammatory cytokines, and 731 immune cell signatures, accessed from the public GWAS Catalog. The primary method employed for MR analysis was Inverse Variance Weighted (IVW). To confirm consistency across results, four supplementary MR methods were also conducted: MR-Egger, Weighted Median, Weighted Mode, and Simple Mode. To assess pleiotropy, we used the MR-Egger regression intercept test and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. Cochrane's Q statistic was applied to evaluate heterogeneity. Additionally, the stability of the MR findings was verified through the leave-one-out sensitivity analysis. This study revealed that interleukin-7 (IL-7) and stem cell growth factor beta (SCGF-β) were possibly associated with the risk of IgAN according to the IVW approach, with estimated odds ratios (OR) of 1.059 (95 % confidence interval [CI] 1.015 to 1.104, P = 0.008) and 1.043 (95 % CI 1.002 to 1.085, P = 0.037). Five immune traits were identified that might be linked to IgAN risk, each with P-values below 0.01, including natural killer T %T cell (OR = 1.058, 95 % CI: 1.020 to 1.097, P = 0.002), natural killer T %lymphocyte (OR = 1.055, 95 % CI: 1.016 to 1.096, P = 0.006), CD25++ CD8+ T cell %T cell (OR = 1.057, 95 % CI: 1.016 to 1.099, P = 0.006), CD3 on effector memory CD4+ T cell (OR = 1.045, 95 % CI: 1.019 to 1.071, P = 0.001), and CD3 on CD28+ CD45RA+ CD8+ T cell (OR = 1.042, 95 % CI: 1.016 to 1.068, P = 0.001). CD4 on central memory CD4+ T cell might be a protective factor for IgAN (OR = 0.922, 95 % CI: 0.875 to 0.971, P = 0.002). Moreover, IgAN may be implicated in a high risk of elevated granulocyte colony-stimulating factor (G-CSF) (OR = 1.114, 95 % CI 1.002 to 1.239, P = 0.046). Our study revealed exposures among typical inflammation markers, inflammatory cytokines, and immune cell signatures that may potentially linked to IgAN risk by MR analysis. This insight may advance our understanding of the etiology of IgAN and support the development of targeted therapeutic strategies.

Ren Y ，Zhang H 《-》

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

Song S ，Sun Y ，Yu J 《-》

Relationship between immune cells and diabetic nephropathy: a Mendelian randomization study.

Although previous studies have suggested potential correlations between immunocytes and diabetic nephropathy (DN), the causal correlations between them remain unclarified. In this study, we employed Mendelian randomization (MR) to analyze the potential causative correlations between immune 731 cells and DN. We used the Genome-Wide Association Studies (GWAS) database to aggregate signatures of immune cells and DN from European and East Asian populations. Single-nucleotide polymorphisms (SNPs) were used as instrumental variables. MR analysis was conducted using Mendelian randomization-Egger (MR-Egger) regression and the random-effects inverse-variance weighted (IVW) method. A total of 3,571 SNPs were included as instrumental variables. The MR-Egger regression model indicated no genetic pleiotropy (P = 0.6284). The results of the IVW method indicated a statistically significant causal relationship between immune cell HLA-DR on CD14-CD16- (P = 0.029), CD45RA-CD28-CD8 + T cell% T cells (P = 0.0278), CD11c on myeloid dendritic cells (P = 0.0352), HLA-DR on CD14+ monocytes (P < 0.001), CD27 on CD24 + CD27 + B cells (P = 0.0334), CD27 on IgD + CD24 + B cells (P = 0.0137), CD4 on CD39 + CD4 + T cells (P = 0.0347), CD28 on CD39 + CD4 + T cells (P = 0.0414), CD39 on CD39 + CD4 + T cells (P = 0.0426), and DN. Additionally, there was no heterogeneity in SNPs related HLA-DR on CD14-CD16-cells and DN(I2 = 32%, Cochran's Q = 2.9476, P = 0.2291). Moreover, leave-one-out analysis showed a causal correlation between HLA-DR on CD14-CD16- cells and DN. Higher expression of immune cell HLA-DR on CD14-CD16- cells may indicate a lower risk of DN.

Li X ，Zhang L ，Yan C ，Zeng H ，Chen G ，Qiu J ... -  《-》

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

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. 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. 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. 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.

Wang SY ，Yu Y ，Ge XL ，Pan S ... -  《Frontiers in Endocrinology》