Global Burden of Periodontitis and Causal Links with Sleep Disorders: A Mendelian Randomization and Multi-Omics Analysis with Focus on Lactylation-Mediated Mechanisms

Background Periodontitis and insomnia represent two prevalent chronic conditions with substantial global health impact. Emerging evidence suggests potential bidirectional relationships between these conditions, yet causal mechanisms remain poorly understood. Methods We conducted a comprehensive three-pronged analysis using Global Burden of Disease (GBD) 2021 data to quantify periodontitis burden across 204 countries and territories from 1990–2021. Two-sample Mendelian randomization (MR) analyses were performed to investigate causal relationships between sleep-related phenotypes and periodontitis risk using large-scale GWAS summary statistics. Multi-omics bioinformatics approaches integrated periodontitis transcriptomic data with insomnia-associated and lactylation-related gene sets to elucidate shared molecular mechanisms. Results Global analysis revealed a 44% increase in absolute periodontitis burden (12.8 to 18.4 million DALYs) despite modest improvements in age-standardized rates (-0.34% annually). Pronounced regional disparities persisted, with Sub-Saharan Africa and South Asia bearing disproportionate burden. MR analysis identified insomnia as a primary causal risk factor for periodontitis (OR = 1.245, 95% CI: 1.016–1.526, P = 0.034 in multivariable analysis), with effect sizes comparable to established risk factors. Educational attainment demonstrated robust protective effects (15.7% risk reduction per additional year). Transcriptomic analysis identified 25 cross-talk genes predominantly enriched in inflammatory pathways, including IL1B, CXCL8, and AGE-RAGE signaling. Novel lactylation-mediated epigenetic regulation was revealed through correlations between transcriptional regulators XBP1/MEF2C and lactylation enzymes HDAC1/SIRT1. Five core biomarkers showed excellent diagnostic performance (AUC > 0.7), with CD93 demonstrating superior discriminatory capacity (AUC = 0.879). Conclusions This study establishes sleep disorders as major modifiable risk factors for periodontitis, with robust causal evidence and molecular validation. The identification of lactylation-mediated epigenetic mechanisms provides novel therapeutic targets. Integration of sleep assessment into periodontal care represents a paradigm shift toward precision oral health interventions addressing upstream determinants of disease.