The genes associated with Sjögren syndrome (SS) can be assigned to the NF-kB pathway, the IFN signaling pathway, lymphocyte signaling, and antigen presentation. The frequencies of risk variants show they are common with modest genetic effects. The strongest genetic association outside the human leukocyte antigen region is in IRF5, a gene relevant in the IFN signaling pathway and for B cell differentiation. Although no association has been found with the NF-kB gene itself, associations in TNFAIP3 and TNIP1 (both genome-wide significant), VCAM1 and IRAK1BP (both suggestive), point to genetic explanations for dysregulation of the NF-kB pathway in SS.
Key points
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The genes associated with Sjögren syndrome can be assigned to the NF-kB pathway, the IFN signaling pathway, lymphocyte signaling, and antigen presentation.
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The frequencies of risk variants show they are common with modest genetic effects, although several genes within the same pathway indicate its importance in disease pathology.
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The strongest genetic association outside the human leukocyte antigen region is in the IRF5, a gene relevant in the IFN signaling pathway and for B cell differentiation.
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Although no association has been found with the NF-kB gene itself, associations in TNFAIP3 and TNIP1 (both genome-wide significant), VCAM1 and IRAK1BP (both suggestive), point to genetic explanations for dysregulation of the NF-kB pathway in SS.
As early as 1937, Lisch suggested a hereditary link in Sjögren syndrome (SS), and indeed 35% of SS patients have relatives with other autoimmune diseases. Early candidate gene studies were largely based on testing risk genes identified in other autoimmune diseases. Most studies have reported initial evidence for association that have not been confirmed in the larger association studies. Substantial overlap has been observed in genes associated with other autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis, indicating common mechanisms that lead to autoimmunity. The genetic loci implicated in autoimmunity affect cell signaling pathways, such as cytokines and cytokine receptors, and intracellular signaling pathways, such as ubiquitination and JAK/STAT kinases, likely resulting in altered protein expression or function. Recent studies in SLE have identified a growing number of causative alleles and functional effects. For example, SLE risk variants that affect expression of RNA transcript levels have been identified for ETS1, SMG7, TNFAIP3, and BLK. Alternative mechanisms have been described, including amino acid changes that affect ligand binding (ITGAM) or regulation of signaling cascades in lymphocyte activation (PTPN22). With over 100 genetic variants now associated with SLE, the functional consequence of many remain elusive. More recently, large-scale genetic association studies have been conducted in SS patients. The most significant associations in SS can be grouped according to their possible functions and mechanisms of actions ( Box 1 ; Fig. 1 ) and are the focus of this article.
