Causal relationships between Epstein-Barr virus infection and sarcopenia: A bidirectional Mendelian randomization study.

Objective: Sarcopenia is a progressive and generalized skeletal muscle disorder defined by age-related low muscle mass, strength, and function. However, the association between Epstein-Barr virus (EBV) infections and sarcopenia remains unclear.

Methods: This bidirectional Mendelian randomization (MR) study investigated causal relationships between EBV-specific antibody traits (EA-D, EBNA-1, VCA p18 and ZEBRA antibodies) and six sarcopenia-related traits (appendicular lean mass, usual walking pace, left hand grip strength, right hand grip strength, whole body fat-free mass and able to walk or cycle unaided for 10 minutes). We employed generalized summary-based MR (GSMR) as the primary analysis, validated by inverse-variance weighted (IVW) and sensitivity analyses. Instrumental variables were rigorously selected to minimize pleiotropy, with mediation analysis assessing immune cell involvement.

Results: Elevated EBV EBNA-1 antibody levels demonstrated robust causal associations with reduced walking speed (GSMR OR=0.9820, P = 0.0004; IVW OR=0.9813, P = 0.0001), and EBV ZEBRA antibody levels correlated with decreased appendicular lean mass (GSMR OR=0.9486, P = 6.46E-15; IVW OR=0.9562, P = 0.0002). Reverse MR revealed limited causal effects of sarcopenia traits on EBV serology, notably whole body fat-free mass increasing EBV VCA p18 antibodies (GSMR OR=1.1350, P = 0.0372; IVW OR=1.2943, P = 0.0469). Sensitivity analysis further confirmed the robustness of these findings. Although no significant immune cell mediation was detected, serveral immunophenotypes potentially mediated the effect of EBV EBNA-1/ZEBRA antibody levels on sarcopenia.

Conclusion: Our findings establish EBNA-1 and ZEBRA antibodies as causal risk factors for sarcopenia. These results position EBV serology as a potential biomarker for sarcopenia risk stratification and therapeutic targeting.