Associations of Herpes Simplex Virus Type 1/2 IgG Seropositivity and Arthritis Subtypes: Integrating Cross‐Sectional Epidemiology and Genetic Association Analyses

Herpes simplex viruses (HSV) have been detected within the synovial joint cavity, a secluded area of inflammation that may harbor etiological agents. However, the role of HSV-1/2 infection in arthritis pathogenesis remains ambiguous. In this study, we integrate cross-sectional epidemiology and genetic associations to elucidate their relationships and uncover causal mechanisms. We analyzed cross-sectional data from 18,292 NHANES participants (1999-2016) using multivariable-adjusted logistic regression to assess associations between anti-HSV-1/2 IgG seropositivity and arthritis-related risks. Complementary analyses included linkage disequilibrium score regression (LDSC) and bidirectional Mendelian randomization (MR) using genetic instruments for anti-HSV IgG levels to explore genetic correlations and infer causality. Initial observational findings demonstrated significant positive associations between HSV-1/2 IgG seropositivity and arthritis risk (all p < 0.001); however, these associations lost significance after multivariable adjustment. Notably, after multivariable adjustment, subtype analyses revealed that HSV-2 IgG seropositivity was linked to increased risks of rheumatoid arthritis (RA) (OR: 1.40, 95% CI: 1.04-1.88) and osteoarthritis (OA) (OR: 1.39, 95% CI: 1.07-1.81), while HSV-1 IgG seropositivity correlated with an unknown-arthritis subtype (OR: 1.38, 95% CI: 1.08-1.75). Moreover, MR analyses uncovered divergent causal effects: anti-HSV-1 IgG levels were protective against OA (OR: 0.90, 95% CI: 0.82-0.98), whereas anti-HSV-2 IgG levels modestly increased OA risk (OR: 1.05, 95% CI: 1.01-1.09). No reverse causation or genetic correlation was observed. This study's innovative integration of epidemiological and genetic methodologies not only clarifies the distinct roles of HSV sub-types in arthritis but also identifies HSV-2 as a potential causal factor in OA, thereby opening new avenues for therapeutic targeting.