No association between anti-cytomegalovirus seropositivity and arthritis: evidence from the cross-sectional epidemiology and genetic association analyses

Human cytomegalovirus (CMV), a β-herpesvirus associated with chronic inflammation and lifelong latency, has been implicated in the pathogenesis of arthritis. However, the nature of this relationship remains controversial. In this study, we integrate cross-sectional epidemiology analyses, genetic correlation assessments, and Mendelian randomization (MR) approaches to elucidate the potential association between CMV infection and arthritis-related conditions. Observational analysis of 5133 participants from the NHANES database revealed a positive association between CMV IgG seropositivity and arthritis (OR: 1.24; 95 % CI: 1.03–1.48; P = 0.02), particularly with the rheumatoid arthritis (RA) subtype (OR: 1.94; 95 % CI: 1.21–3.12; P < 0.01). However, these associations lost statistical significance after adjustment for multiple covariates (all P > 0.05). Subgroup and interaction analyses across different demographic and clinical subpopulations further confirmed the absence of these associations. Similarly, subtype analyses indicated no significant association between CMV IgG seropositivity and osteoarthritis (OA), other-arthritis, or unknown-arthritis, even before covariate adjustment. Linkage disequilibrium score regression (LDSC) analysis did not reveal a significant genetic correlation between anti-CMV IgG levels and arthritis, including RA and OA (all P > 0.05), suggesting no shared genetic basis. Furthermore, bidirectional MR analyses found no evidence of a causal relationship between CMV antibody responses—including IgG and three CMV-related peptide antigens (pp28, pp52, and pp150)—and arthritis, RA, or OA (all P > 0.05). Collectively, these findings suggest that previously reported positive associations between CMV seropositivity and arthritis may have been confounded by other covariates rather than reflecting a true causal relationship.