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

Shang-Yuan Wang; Yang Yu; Xiao-Li Ge; Shuming Pan

doi:10.3389/fendo.2024.1357642

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

Front Endocrinol (Lausanne). 2024 Sep 13:15:1357642. doi: 10.3389/fendo.2024.1357642. eCollection 2024.

Authors

Shang-Yuan Wang¹, Yang Yu¹, Xiao-Li Ge¹, Shuming Pan¹

Affiliation

¹ Department of Emergency Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

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.

Keywords: HLA-DR; Mendelian randomization; dendritic cells; diabetic nephropathy; immune cells; monocyte.

MeSH terms

Dendritic Cells / immunology
Diabetic Nephropathies* / genetics
Diabetic Nephropathies* / immunology
Genetic Predisposition to Disease
Humans
Mendelian Randomization Analysis*
Polymorphism, Single Nucleotide

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by National Natural Science Foundation of China (82072207, 81971861); and Shanghai Municipal Science and Technology Commission Shanghai Excellent Discipline Leader Program (21XD1402200).