Abstract
BACKGROUND: Previous observational studies have indicated an association between serum uric acid (SUA) and diabetic neuropathy (DN), but confounding factors and reverse causality have left the causality of this relationship uncertain. METHODS: Univariate Mendelian randomization (MR), multivariate MR and linkage disequilibrium score (LDSC) regression analysis were utilized to assess the causal link between SUA and DN. Summary-level data for SUA were drawn from the CKDGen consortium, comprising 288,648 individuals, while DN data were obtained from the FinnGen consortium, with 2,843 cases and 271,817 controls. Causal effects were estimated primarily using inverse variance weighted (IVW) analysis, supplemented by four validation methods, with additional sensitivity analyses to evaluate pleiotropy, heterogeneity, and result robustness. RESULTS: The LDSC analysis revealed a significant genetic correlation between SUA and DN (genetic correlation = 0.293, P = 2.60 × 10(-5)). The primary methodology IVW indicated that each increase of 1 mg/dL in SUA would increase DN risk by 17% (OR = 1.17, 95% CI 1.02-1.34, P = 0.02), while no causal relationship was found in reverse analysis (OR = 1.00, 95% CI 0.98~1.01, P = 0.97). Multivariate MR further identified that the partial effect of SUA on DN may be mediated by physical activity, low density lipoprotein cholesterol (LDL-C), insulin resistance (IR), and alcohol use. CONCLUSION: The study establishes a causal link between elevated SUA levels and an increased risk of DN, with no evidence for a reverse association. This underscores the need for a comprehensive strategy in DN management, integrating urate-lowering interventions with modulations of the aforementioned mediators.