Abstract
Sjögren's disease (SD) is an autoimmune disorder characterized by dysregulated interferon (IFN) signaling, but the causal genes and regulatory mechanisms remain unclear. We integrated transcriptomic, epigenomic, and genetic data using summary data-based Mendelian randomization (SMR) and colocalization analyses. A meta-analysis of three datasets (N = 124) identified 331 differentially expressed IFN-associated genes enriched in immune cells. SMR analysis of blood and minor salivary gland (MSG) expression quantitative trait locus (eQTL)/DNA methylation QTL (mQTL) data with the SD genome-wide association study (GWAS) identified five causal genes: SH2B3, LGALS9, CD40, GRB2, and DTX3L. DNA methylation at specific CpG sites regulated the expression of SH2B3 and LGALS9. Colocalization revealed that these genes interact with inflammatory cytokines, including C-C motif chemokine 19 (CCL19), interleukin-2 receptor subunit beta (IL-2Rβ), IL-10, and CCL4. Enzyme-linked immunosorbent assay (ELISA) validation in 16 patients with SD confirmed elevated serum levels. This study elucidates the epigenetic regulation of IFN-associated genes in SD pathogenesis and identifies potential therapeutic targets.