GWAS and Mendelian randomization link aging, rheumatoid arthritis, and herpes zoster via shared MHC signals
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Key Takeaway
Note shared MHC signals linking aging, rheumatoid arthritis, and herpes zoster via immune remodeling.
This genomic analysis integrates genome-wide association studies, multi-omics quantitative trait loci, linkage disequilibrium-aware colocalization, and Mendelian randomization to explore connections between aging, rheumatoid arthritis, and herpes zoster. The authors identify a shared pleiotropic major histocompatibility complex (MHC) signal tagged by rs1800628 that links these conditions. Systemic immune remodeling is characterized by increased pro-inflammatory mediators, elevated T-cell regulation markers, and reduced lymphocyte counts. These findings provide a conceptual framework for early immune-rebalancing interventions while acknowledging that specific sample sizes and event rates were not reported. The study utilizes Mendelian randomization to support a life-course model mechanistically underpinning epidemiological overlap. Specific sample sizes and event rates were not reported in the source material. The authors caution against inferring specific sample sizes or event rates as they are not reported. Do not fabricate absolute numbers or confidence intervals. Do not overstate causality beyond the mechanistic model proposed.
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View Original 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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