A shared MHC immunogenetic signal links aging, rheumatoid arthritis, and herpes zoster through high inflammatory burden-compensatory immune tolerance dysregulation
Abstract
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 scans 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, predisposing individuals to both autoimmunity and VZV reactivation. Collectively, our findings support a life-course "high inflammatory burden-compensatory immune tolerance dysregulation" model that mechanistically underpins the broader epidemiological overlap of aging, autoimmunity, and HZ, providing a conceptual framework for early immune-rebalancing interventions.
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Research summary
The paper identifies a shared genetic signal linking aging, rheumatoid arthritis, and herpes zoster, suggesting a model for immune dysregulation in aging. The research addresses underlying mechanisms that connect aging with autoimmune diseases, contributing to the understanding of age-related immune system changes.
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