Ye Xinjian, Yuan Jian, Bai Yijing, Chen Yitong, Jiang He, Cao Yue, Ge Qifei, Wang Zhiyong, Pan Weiyi, Wang Shan, Chen Qianming
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 Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China.
The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
J Periodontol. 2024 Nov 4. doi: 10.1002/JPER.24-0300.
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.
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.
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) and demonstrate a significant genetic correlation (p = 4.11 × 10). 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).
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.
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.
牙周炎源于环境变量与遗传易感性的多方面相互作用，其中微生物感染起着不可或缺的作用。长期以来，爱泼斯坦-巴尔病毒（EBV）暴露一直被认为与牙周炎活动有关；然而，它们之间的因果关系和遗传联系仍然未知。
在生命历程的背景下，我们的研究采用了综合孟德尔随机化（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联。此外，利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，随后进行全转录组关联和富集分析，以识别遗传-表型生物学特征。
EBV抗体水平升高，特别是早期抗原扩散（作为早期感染或再激活的指标），与牙周炎风险增加相关（优势比[OR]：1.27[1.09 - 1.47]，p = 6.05×10），并显示出显著的遗传相关性（p = 4.11×10）。这种发病机制可能涉及位于17p13.1的高可信度因果基因RNASEK。遗传预测的早年抗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）。
本研究强调了生命历程中EBV暴露及其遗传特征对牙周炎的影响，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。这些发现强调了多种临床和公共卫生意义，包括抗病毒治疗、病毒疫苗接种策略以及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。
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。虽然传统上细菌一直是研究的重点，但最近的研究强调了病毒-细菌相互作用的重要性，特别是爱泼斯坦-巴尔病毒（EBV）——一种感染全球超过90%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。我们发现近期的EBV感染或再激活会增加牙周炎的风险，而早年暴露可能产生免疫抵抗，从而降低风险。确定了关键基因作为潜在的介导因子，包括CRTC3-AS1、HLA-DQA1和RNASEK。这些发现为EBV与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，通过疫苗接种进行早期病毒暴露可能降低牙周炎的风险。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。
