Selected genes with polymorphisms associated with Sjögren's disease in genome-wide association studies

Gene name or region	Comments
Human leukocyte antigen (HLA)	The HLA region has the strongest signal in genome-wide association studies (GWAS), particularly the ancestral haplotype of DRB10201, DQB10201, and DQA10501. However, the recognition of RFX5*, a key transcriptional regulator of the HLA class II loci, extended previous HLA associations.
IRF5	IRF5 is a member of the interferon regulatory factor (IRF) family, a group of transcription factors with diverse roles including virus-mediated activation of interferon and modulation of cell growth, differentiation, apoptosis, and immune system activity.
STAT4	STAT4 genes lie next to the STAT1 gene locus, suggesting that the genes arose by gene duplication. STAT proteins have several functional domains, including an N-terminal interaction domain, a central DNA-binding domain, an SH2 domain, and the C-terminal trans-activation domain.
IL12A	Two chains of the interleukin (IL)-12 receptor form a heterodimer after IL-12 binding and activate the receptor-associated Janus kinases, termed JAK2 and TYK2. STAT4 is phosphorylated by these tyrosine kinases, homodimerizes via its SH2 domain, and translocates into the nucleus to activate gene transcription.
BLK	Tyrosine-protein kinase, also known as B lymphocyte kinase.
TNIP1	TNIP1 has been shown to interact with TNFAIP3 and MAPK that are both rapidly induced by tumor necrosis factor (TNF) and inhibit NF-kappa B activation as well as TNF-mediated apoptosis. Knockout studies of a similar gene in mice suggested that this gene is critical for limiting inflammation by terminating TNF-induced NF-kappa B responses.
CXCR5	Also known as Burkitt lymphoma receptor 1 (BLR1). The CXCR5 gene is specifically expressed in follicles in lymph nodes. The gene plays an essential role in B-cell migration.

These results highlight the importance of genes that promote innate immunity (type 1 interferon signature) and acquired immunity (HLA-linked recognition of antigen by T and B cells through traditional antigen-presenting pathways). One interesting observation is that CXCR5, a homing receptor, was not found in GWAS of systemic lupus erythematosus (SLE) patients. This is one of the few examples where SLE and Sjögren's disease can be differentiated on a genetic basis and helps explain the relative organ specificity and lymphoproliferative nature of Sjögren's disease.

Source: Nocturne G, Mariette X. Advances in understanding the pathogenesis of primary Sjögren's syndrome. Nat Rev Rheumatol 2013; 9:544.

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Selected genes with polymorphisms associated with Sjögren's disease in genome-wide association studies