Genetic Evidence Supporting Causal Associations Between Viral Infections and Sjogren's Syndrome

Background Sjogren's syndrome (SS) is a chronic inflammatory autoimmune disorder that mainly targets exocrine glands. Previous studies have suggested potential associations between Epstein-Barr virus (EBV), hepatitis virus (HAV), and other viruses with SS, but the causal nature of these relationships remains uncertain. This study used Mendelian randomisation (MR) to examine the genetic causal association between viral infections and SS. Methods Genetic data for SS was sourced from a genome-wide association study (GWAS) database of individuals of European ancestry (1290 patients and 213,415 healthy controls). Genetic data for nine viruses, including EBV, HAV, COVID-19, human immunodeficiency virus(HIV), cytomegalovirus, influenza virus, Coxsackie virus, measles virus, and retrovirus, were obtained from the IEU Open GWAS. Inverse variance weighting (IVW) served as the primary analysis method for MR Analysis, with Wald ratio, MR Egger, and weighted as supplementary analyses. Results MR analysis revealed causal associations between SS and five viral infections. Elevated VCA p18 antibodies against EBV, HAV, and COVID-19 were associated with increased SS risk, with respective odds ratios (OR) of 1.270 (95% CI: 1.043–1.550, p = 0.016), 1.163 (95% CI: 1.035–1.317, p = 0.009), and 1.109 (95% CI: 1.024–1.209, p = 0.013). Conversely, IgG antibodies against EBV and human immunodeficiency virus were associated with the reduction of SS risk, with ORs of 0.632 (95% CI: 0.430–0.921, p = 0.016) and 0.875 (95% CI: 0.787–0.972, p = 0.016) respectively. Sensitivity analysis did not reveal significant heterogeneity or horizontal pleiotropy. No statistically significant associations were found between the other four viruses and SS risk (all p > 0.05). Conclusion Our findings suggest that genetically predicted elevated levels of VCA p18 antibodies against EBV, HAV, and COVID-19 increase the risk of SS, while IgG antibody levels against EBV and HIV may confer protection. This study provides additional evidence for a link between viral infection and SS, aiding clinicians in identifying potential causative factors and thereby enhancing diagnostic specificity and sensitivity.