Causal Relationship Between Serum Zinc Levels and Diabetic Kidney Disease (DKD): A Plasma Proteomics Mediation Study

The association between serum zinc levels and diabetic kidney disease (DKD) has been a focus of considerable scientific interest. Lower serum zinc has been observed to be involved in the progression of DKD, and zinc supplementation can improve the kidney damage of DKD. However, the causal link and the underlying mechanisms driving this association remain poorly understood. A two-sample Mendelian randomization (MR) study was conducted to explore the causal relationship between serum zinc levels and the incidence of DKD. Single nucleotide polymorphisms (SNPs) meeting the inclusion criteria were selected as instrumental variables. Analytical methods included inverse variance weighting (IVW), MR-Egger regression, and sensitivity analysis to ensure the robustness of the results. A subsequent pathway MR analysis was performed using plasma proteomics to identify proteins significantly associated with the outcome, followed by metabolic or signaling pathway enrichment analysis. This study found that lower serum zinc levels were associated with an increased risk of DKD (OR (95% CI): 0.886 (0.854-0.920), p < 0.001). In the mediation analysis, 26 plasma proteins were identified as mediators of this association, including N-terminal Xaa-Pro-Lys N-methyltransferase 1, Multiple PDZ domain protein, Asialoglycoprotein receptor 1, and Cilia- and flagella-associated protein 45, among others. These proteins mediated the relationship between lower serum zinc levels and the increased risk of DKD, with the mediation effect ranging from 3.31 to 22.06%. Furthermore, four key signaling or metabolic pathways were identified: Digestion, Events associated with phagocytolytic activity of PMN cells, Digestion and absorption, and DSCAM interactions, all of which were involved in mediating the association between decreased serum zinc levels and the development of DKD. The present findings have elucidated the underlying mechanism through which lower serum zinc levels contribute to the development of DKD, thereby providing a foundation for future research in this area.