Appraising the life‐course impact of Epstein‐Barr virus exposure and its genetic signature on periodontitis

Abstract Background Periodontitis arises from a multifaceted interplay of environmental variables and genetic susceptibility, where microbial infection plays an indispensable part. Epstein‐Barr virus (EBV) exposure has long been considered associated with periodontitis activity; however, the causal relationship and genetic connection between them remain unknown. Methods Within a life‐course context, our study employed comprehensive Mendelian randomization (MR) methods, including univariable, multivariable, Bayesian model averaging, and reverse MR, to investigate the causal association between EBV exposure and periodontitis. Additionally, linkage disequilibrium score regression and colocalization analysis were utilized to assess the cross‐trait genetic correlations, followed by transcriptome‐wide association and enrichment analysis to discern the genetic‐phenotypic biological profiles. Results Heightened levels of EBV antibodies, particularly early antigen diffuses (which serve as indicators of early infection or reactivation), are associated with an increased risk of periodontitis (odds ratio [OR]: 1.27 [1.09–1.47], p = 6.05 × 10 −3 ) and demonstrate a significant genetic correlation ( p = 4.11 × 10 −3 ). This pathogenesis may involve the high‐confidence causal gene RNASEK located in 17p13.1. Genetically predicted early‐life anti‐EBV immunoglobulin G (IgG) levels are correlated to a reduced periodontitis risk (OR: 0.89 [0.82–0.97], p = 1.76 × 10 −3 ). Conclusions The present study highlights the impact of life‐course EBV exposure and its genetic hallmark on periodontitis, providing novel perspectives into the underlying pathogenesis and management strategies for EBV‐related periodontitis. These findings underscore diverse clinical and public health implications, encompassing antiviral therapies, viral vaccination strategies, and tailored interventions for individualized periodontitis management. Further research is required to validate and expand upon our findings. Plain Language Summary Periodontitis is a chronic inflammatory disease driven by interactions between microbial pathogens and the host immune system. While bacteria have traditionally been the focus of research, recent studies highlight the significance of virus‐bacteria interactions, particularly the role of Epstein‐Barr virus (EBV)—a herpesvirus infecting over 90% of the global population—in the development of periodontitis. However, the underlying causal and genetic mechanisms remain unclear. Our study employed genome‐wide multi‐omics approaches to investigate the link between EBV exposure and periodontitis. We found that recent EBV infection or reactivation increases the risk of periodontitis, whereas early‐life exposure, possibly enabling immune resistance, may reduce it. Essential genes were identified as potential mediators, including CRTC3‐AS1 , HLA‐DQA1 , and RNASEK . These findings provide novel insights into the EBV‐periodontitis connection. For example, viral testing and control could benefit patients unresponsive to standard bacterial treatments, and early viral exposure via vaccination might reduce the risk of periodontitis. Further clinical studies are required to elucidate these underlying mechanisms and the contribution of virus‐bacteria interactions.