Causal Effects of Type 2 Diabetes Mellitus on Chronic Periodontitis and the Mediating Role of Oxidative Stress: Evidence From Mendelian Randomization and Mediation Analysis

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of chronic periodontitis, but genetic evidence and oxidative stress-related pathways remain unclear. OBJECTIVE: This study assessed the genetically inferred association between T2DM and chronic periodontitis, evaluated oxidative stress biomarkers as potential mediators, and explored potential biological pathways. METHODS: Two-sample univariable Mendelian randomization (MR) was performed using public GWAS summary data for T2DM, 11 oxidative stress biomarkers, and chronic periodontitis. Candidate biomarkers were further assessed using multivariable MR and mediation analysis. Gene mapping and functional enrichment were performed to provide biological context. RESULTS: Genetically predicted T2DM was associated with increased risk of chronic periodontitis in inverse-variance weighted analysis, with a modest effect estimate (OR = 1.1056, 95% CI: 1.0333~1.1829, p = 0.004). Uric acid emerged as the main candidate biomarker associated with both T2DM and chronic periodontitis. Mediation analysis suggested a negative mediated proportion through uric acid (-7.94%), indicating a suppressive or counteracting pattern. Functional enrichment highlighted pathways related to insulin secretion, protein transport, and cellular homeostasis. CONCLUSIONS: This study provides supportive genetic evidence for a modest T2DM-chronic periodontitis association. Uric acid may be involved in a complex redox- and metabolism-related pathway, but this finding requires further validation.