Dissecting the causal association of periodontitis with biological aging and its underlying mechanisms: findings from Mendelian randomization and integrative genetic analysis.

Abstract

Purpose: Chronic low-grade inflammation is linked to the biology of aging; however, evidence supporting a causal relationship between periodontitis-a dysbiotic biofilm-initiated inflammatory disease-and accelerated aging remains limited. This study investigated the causality between periodontitis and biological aging and identified potentially shared genomic loci, genes, and pathways.

Methods: We conducted a 2-sample Mendelian randomization (MR) analysis to explore the causality of periodontitis on age acceleration measures (DNAm PhenoAge acceleration, GrimAge acceleration, Hannum age acceleration, and intrinsic epigenetic age acceleration) using a dataset from genome-wide association studies of European ancestry populations. Independent genetic variants associated with each trait were used as instrumental variables. The inverse variance-weighted (IVW) method served as the primary MR approach, supplemented by sensitivity testing. We also performed additional statistical genetic analyses to identify pleiotropic loci, shared functional genes, and potential biological pathways, integrating large-scale expression quantitative trait loci data from blood samples.

Results: The MR analysis indicated a causal relationship between periodontitis and DNAm PhenoAge acceleration (IVW β=0.308; 95% confidence interval, 0.056-0.561; P=0.017), a finding corroborated by sensitivity analyses. There was a significant genetic overlap between periodontitis and age acceleration. Pleiotropic analysis revealed 24 shared SNPs associated with 242 genes, predominantly involved in immune functions and pathways related to cellular processes. Further integration analysis showed that 91 of these pleiotropic genes were causally linked to both conditions, with C6orf183 identified as a potential mediator.

Conclusions: This study presents compelling genetic evidence supporting a causal relationship between periodontitis and accelerated aging. Further research is required to validate these findings and investigate the underlying mechanisms.