BackgroundPeriodontitis 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.MethodsWithin 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.ResultsHeightened 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).ConclusionsThe 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 SummaryPeriodontitis 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.

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评价 Epstein-Barr 病毒暴露及其遗传特征对牙周炎的生命全程影响


背景 牙周炎是由环境变量和遗传易感性多方面的相互作用引起的，其中微生物感染起着不可或缺的作用。长期以来，人们一直认为 EB 病毒 （EBV） 暴露与牙周炎活动有关;然而，它们之间的因果关系和遗传联系仍然未知。方法在生命历程背景下，我们的研究采用了全面的孟德尔随机化 （MR） 方法，包括单变量、多变量、贝叶斯模型平均和反向 MR，以研究 EBV 暴露与牙周炎之间的因果关系。此外，采用连锁不平衡评分回归和共定位分析来评估跨性状遗传相关性，然后进行转录组范围的关联和富集分析以识别遗传表型生物学特征。结果EBV 抗体水平升高，尤其是早期抗原弥散（作为早期感染或再激活的指标），与牙周炎风险增加相关（比值比 [OR]：1.27 [1.09–1.47]，p = 6.05 × 10-3），并显示出显著的遗传相关性 （p = 4.11 × 10-3）。这种发病机制可能涉及位于 17p13.1 的高可信度致病基因 RNASEK。遗传预测的早期抗 EBV 免疫球蛋白 G （IgG） 水平与牙周炎风险降低相关 （OR： 0.89 [0.82–0.97]，p = 1.76 × 10-3）。结论本研究强调了生命历程 EBV 暴露及其遗传标志对牙周炎的影响，为 EBV 相关牙周炎的潜在发病机制和管理策略提供了新的视角。 这些发现强调了不同的临床和公共卫生影响，包括抗病毒疗法、病毒疫苗接种策略和针对个体化牙周炎管理的定制干预措施。需要进一步的研究来验证和扩展我们的发现。通俗易懂的牙周炎是一种由微生物病原体与宿主免疫系统相互作用驱动的慢性炎症性疾病。虽然细菌传统上是研究的重点，但最近的研究强调了病毒与细菌相互作用的重要性，特别是 EB 病毒 （EBV）（一种感染全球 90% 以上人口的疱疹病毒）在牙周炎发展中的作用。然而，潜在的因果和遗传机制仍不清楚。我们的研究采用全基因组多组学方法来研究 EBV 暴露与牙周炎之间的联系。我们发现，近期 EBV 感染或再激活会增加患牙周炎的风险，而早期接触可能会使免疫抵抗力降低。必需基因被确定为潜在介质，包括 CRTC3-AS1 、 HLA-DQA1 和 RNASEK。这些发现为 EBV-牙周炎的联系提供了新的见解。例如，病毒检测和控制可能使对标准细菌治疗无反应的患者受益，而通过疫苗接种早期接触病毒可能会降低患牙周炎的风险。需要进一步的临床研究来阐明这些潜在机制以及病毒-细菌相互作用的贡献。