A shared MHC immunogenetic signal links aging, rheumatoid arthritis, and herpes zoster through high inflammatory burden-compensatory immune tolerance dysregulation

Epidemiological studies link aging and autoimmune diseases to increased herpes zoster (HZ) risk, yet their shared genetic basis remains unresolved. Here, we integrated large-scale genome-wide association studies (GWAS) of a multivariate aging latent factor (mvAge), rheumatoid arthritis (RA, representing autoimmunity), and HZ with multi-omics quantitative trait loci. Using linkage disequilibrium-aware colocalization and Mendelian randomization (MR), we identified a shared pleiotropic major histocompatibility complex (MHC) signal, tagged by rs1800628. Phenome-wide association studies (PheWAS) and network analyses revealed that the signal drives systemic immune remodeling, characterized by increased pro-inflammatory mediators, elevated T-cell regulation markers, and reduced lymphocyte counts. This pleiotropic genetic variation may alter the lifelong immune regulatory trajectory, accelerating aging and predisposing individuals to both autoimmunity and VZV reactivation. These findings support a life-course "high inflammatory burden-compensatory immune tolerance dysregulation" model that mechanistically underpins the epidemiological overlap of aging, autoimmunity, and HZ, providing a conceptual framework for early immune-rebalancing interventions.