Li Jie, Chen Tailin
Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Lab of Reproduction and Development, Shanghai Key Lab of Female Reproductive Endocrine Related Diseases, Shanghai, China.
Department of Epidemiology, School of Public Health, Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China.
Exp Gerontol. 2025 Oct 1;209:112860. doi: 10.1016/j.exger.2025.112860. Epub 2025 Aug 11.
The causal relationship between Epstein-Barr virus (EBV) infection and frailty or fatigue remains unclear, despite evidence linking chronic inflammation to these conditions.
This study utilized a two-sample Mendelian Randomization (MR) framework to investigate the causal relationship between EBV infection and the development of frailty and fatigue. The outcomes assessed were frailty, defined by the Frailty Index (FI), and fatigue, measured through Chronic Fatigue Syndrome (CFS), Malaise and Fatigue (MF), while EBV infection was represented by anti-EBV IgG seropositivity, antibody levels, and a history of infectious mononucleosis. Genetic variants strongly associated with EBV exposure were identified and used as instrumental variables (IVs). Two-sample MR analyses were conducted using the Inverse Variance Weighted (IVW) method, and multivariable MR (MVMR) was applied to adjust for potential confounding, including age. Reverse MR analyses were also performed to explore reverse causality. Sensitivity analyses, including horizontal pleiotropy and leave-one-out tests, were carried out to assess the reliability of the results.
A total of 9 GWAS were used to derive summary data for EBV-related exposures and frailty/fatigue outcomes. In multivariable MR, EBV ZEBRA antibody levels were significantly associated with an increased FI score (aβ = 0.026; 95 % CI 0.006, 0.046; P = 0.011) after age adjustment. EBV EA-D showed a significant link with CFS in unadjusted models, but lost significance after age adjustment. EBV VCA p18 and EA-D were associated with MF, with significance remaining for EBV VCA p18 (aOR = 1.25; 95 % CI: 1.01, 1.57; P = 0.046) and EA-D (aOR = 1.38; 95 % CI: 1.00, 1.90; P = 0.049) after age adjustment. The reverse MR analysis revealed negative associations between MF and EBNA-1/ZEBRA antibodies. Sensitivity analyses confirmed robustness with no evidence of pleiotropy or heterogeneity. Secondary analysis further supported the causal associations.
EBV infection demonstrates causal links to frailty and fatigue, mediated through specific antibody responses. These findings emphasize EBV's role in chronic inflammatory pathways and highlight potential targets for clinical intervention.
尽管有证据表明慢性炎症与虚弱或疲劳有关，但爱泼斯坦-巴尔病毒（EBV）感染与虚弱或疲劳之间的因果关系仍不清楚。
本研究采用两样本孟德尔随机化（MR）框架，以调查EBV感染与虚弱和疲劳发展之间的因果关系。评估的结果包括由虚弱指数（FI）定义的虚弱，以及通过慢性疲劳综合征（CFS）、不适与疲劳（MF）测量的疲劳，而EBV感染则由抗EBV IgG血清阳性、抗体水平和传染性单核细胞增多症病史来表示。确定了与EBV暴露密切相关的基因变异，并将其用作工具变量（IVs）。使用逆方差加权（IVW）方法进行两样本MR分析，并应用多变量MR（MVMR）来调整潜在的混杂因素，包括年龄。还进行了反向MR分析以探索反向因果关系。进行了敏感性分析，包括水平多效性和留一法检验，以评估结果的可靠性。
总共使用了9项全基因组关联研究（GWAS）来获取EBV相关暴露和虚弱/疲劳结果的汇总数据。在多变量MR中，调整年龄后，EBV ZEBRA抗体水平与FI评分升高显著相关（aβ = 0.026；95%可信区间0.006，0.046；P = 0.011）。在未调整的模型中，EBV EA-D与CFS有显著关联，但调整年龄后失去显著性。EBV VCA p18和EA-D与MF相关，调整年龄后，EBV VCA p18（aOR = 1.25；95%可信区间：1.01，1.57；P = 0.046）和EA-D（aOR = 1.38；95%可信区间：1.00，1.90；P = 0.049）仍具有显著性。反向MR分析显示MF与EBNA-1/ZEBRA抗体之间存在负相关。敏感性分析证实了结果的稳健性，没有多效性或异质性的证据。二次分析进一步支持了因果关联。
EBV感染通过特定的抗体反应显示出与虚弱和疲劳的因果联系。这些发现强调了EBV在慢性炎症途径中的作用，并突出了临床干预的潜在靶点。
