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Abstract

Background: Abnormal activation of the Interferon (IFN) signalling plays a central role in the progression of Sjögren’s Syndrome (SS). However, the causal relationship between IFN signalling and SS remains unclear, with complex interactions existing among genetic variants, epigenetic modifications, inflammatory cytokine levels, and the expression of IFN-associated genes. Thus, in order to reveal the potential causality and interaction mechanisms among IFN-associated gene expression, DNA methylation, inflammatory cytokines, and SS, our analysis was conducted using a multi-omics Summary data-based Mendelian randomization (SMR) approach.

Methods: Genes associated with IFN signalling were extracted from the GeneCards database, and transcriptomic datasets for SS were obtained from the Gene Expression Omnibus (GEO) database. Linear regression models and meta-analysis identified IFN-associated Differentially Expressed Genes (DEGs) in SS. Using a three-step SMR method, an integrated analysis of expression quantitative trait loci (eQTLs) and DNA methylation QTLs (mQTLs) with SS Genome-Wide Association Study (GWAS) from FinnGen was performed to reveal causal relationships between blood IFN-associated gene expression, DNA methylation, and SS pathogenesis. Then use SS GWAS data from UK Biobank for validation. Through colocalization analysis, integrating analysis of blood IFN-associated causal genes eQTLs with inflammatory cytokines GWAS was performed to identify potential interactions between blood IFN gene expression and inflammatory cytokines. Meanwhile, Minor Salivary Gland (MSG) tissue eQTLs from GTEx V8 and SS GWAS were integrated by SMR to identify MSG IFN-associated causal genes. Through colocalization analysis, integrating analysis of MSG IFN-associated causal genes eQTLs with inflammatory cytokines GWAS was performed to identify potential interactions between IFN-associated causal gene expression in MSG and inflammatory cytokines.

Results: A total of 331 IFN-associated DEGs were identified by integrative analysis of three transcriptomic datasets and 711 IFN-associated genes. These DEGs are predominantly enriched in T-cells, macrophages, monocytes, and natural killer cells. Five blood IFN-associated genes: SH2B3, LGALS9, CD40, GRB2, and DTX3L, were identified as SS-causal genes using a three-step SMR approach. Three of these genes, LGALS9, SH2B3, and CD40, are involved in the interaction between gene expression and inflammatory cytokines through colocalization analysis. Furthermore, SMR and colocalization analysis also identified thirteen putative MSG IFN-associated genes, four of which were involved in gene–inflammatory cytokines interactions: APOBEC3G, IFI27L2, TMEM50B, and SH2B3. 

Conclusions: This study uncovered a causal relationship between interferon signalling and SS, revealing complex interactions among IFN-associated causal gene expression, DNA methylation, and inflammatory cytokines in SS pathogenesis. This offers new evidence for the involvement of interferon signalling in the pathogenic process of SS and provides fresh insights into the interactions among epigenetic, genetic variants, and inflammatory cytokines for in-depth studies of pathogenesis and molecular mechanisms.

Keywords: Interferon signaling, Sjogren’s syndrome, Integrative omics, Mendelian randomization, Inflammatory cytokines