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Epstein\u2010Barr virus (EBV) exposure has long been considered associated with periodontitis activity; however, the causal relationship and genetic connection between them remain unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Within a life\u2010course 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\u2010trait genetic correlations, followed by transcriptome\u2010wide association and enrichment analysis to discern the genetic\u2010phenotypic biological profiles.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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\u20131.47],\u00a0<jats:italic>p<\/jats:italic>\u00a0=\u00a06.05\u00a0\u00d7\u00a010<jats:sup>\u22123<\/jats:sup>) and demonstrate a significant genetic correlation (<jats:italic>p<\/jats:italic>\u00a0=\u00a04.11\u00a0\u00d7\u00a010<jats:sup>\u22123<\/jats:sup>). This pathogenesis may involve the high\u2010confidence causal gene <jats:italic>RNASEK<\/jats:italic> located in 17p13.1. Genetically predicted early\u2010life anti\u2010EBV immunoglobulin G (IgG) levels are correlated to a reduced periodontitis risk (OR: 0.89 [0.82\u20130.97],\u00a0<jats:italic>p<\/jats:italic>\u00a0=\u00a01.76\u00a0\u00d7\u00a010<jats:sup>\u22123<\/jats:sup>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The present study highlights the impact of life\u2010course EBV exposure and its genetic hallmark on periodontitis, providing novel perspectives into the underlying pathogenesis and management strategies for EBV\u2010related 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Plain Language Summary<\/jats:title><jats:p>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\u2010bacteria interactions, particularly the role of Epstein\u2010Barr virus (EBV)\u2014a herpesvirus infecting over 90% of the global population\u2014in the development of periodontitis. However, the underlying causal and genetic mechanisms remain unclear. Our study employed genome\u2010wide multi\u2010omics 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\u2010life exposure, possibly enabling immune resistance, may reduce it. Essential genes were identified as potential mediators, including <jats:italic>CRTC3\u2010AS1<\/jats:italic>, <jats:italic>HLA\u2010DQA1<\/jats:italic>, and <jats:italic>RNASEK<\/jats:italic>. These findings provide novel insights into the EBV\u2010periodontitis 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\u2010bacteria interactions.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jper.24-0300","type":"journal-article","created":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T07:35:45Z","timestamp":1730705745000},"page":"717-730","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Appraising the life\u2010course impact of Epstein\u2010Barr virus exposure and its genetic signature on periodontitis"],"prefix":"10.1002","volume":"96","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2300-6117","authenticated-orcid":false,"given":"Xinjian","family":"Ye","sequence":"first","affiliation":[{"name":"Stomatology Hospital School of Stomatology Zhejiang University School of Medicine Zhejiang Provincial Clinical Research Center for Oral Diseases Key Laboratory of Oral Biomedical Research of Zhejiang Province Cancer Center of 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