Genome-wide association studies in Sjögren's syndrome: What do the genes tell us about disease pathogenesis?

Abstract

The pathogenesis of Sjögren's syndrome (SS) likely involves complex interactions between genes and the environment. While the candidate gene approach has been previously used to identify several genes associated with SS, two recent large-scale genome-wide association studies (GWAS) have implicated many more loci as genetic risk factors. Of particular relevance, was the significant association of SS with additional immune-related genes including IL12A, BLK, and CXCR5. GWAS has also uncovered other loci and suggestive gene associations in SS, but none are related to genes encoding salivary or lacrimal components, secretion machinery and neuronal proteins involved in innervations of the glands, respectively. In this review, we discuss these genetic findings with particular attention paid to the genes identified, the strength of associations, and how the SS-associated genes compare to what has been discovered previously in systemic lupus erythematosus (SLE). We also summarize the potential impact of these associated gene products on NFκB and immune pathways and describe how this new information might be integrated further for identifying clinical subsets and understanding the pathogenesis of SS.

Keywords: Autoimmune disease; Candidate genes; Genetics; Genome-wide association studies; Polymorphisms; SNP; Sjögren's syndrome.

Figure 1. Functional pathways potentially altered in SS identified by GWAS

The eight genes associated with SS that were identified by GWAS (labeled in blue) play a role in immune function and NFkB signaling. Alterations of the eight genes likely impact at least three key cellular activities: antibody production/clearance, cytokine production and proliferation of immune cells. In this model, subjects harboring these polymorphisms are more likely to develop an exaggerated inflammatory response following infection and other environmental triggers. Consequently, the activation of plasmacytoid dendritic cells, T-cells, B–cells and other immune cells cause the destruction of the salivary gland and its normal function.