STAT4 is a confirmed genetic risk factor for Sjögren's syndrome and could be involved in type 1 interferon pathway signaling

Abstract

Signal transducer and activator of transcription 4 (STAT4) is a transcription factor mainly activated by interleukin 12, which promotes the secretion of type 2 interferon (IFN) by T-helper 1 cells. We assessed the association of STAT4 gene polymorphism and primary Sjö gren's syndrome (pSS) and its functional relevance. We analyzed STAT4 rs7582694 polymorphism in an exploratory cohort of 186 pSS patients and 152 controls, and in a replication cohort of 192 pSS patients and 483 controls, all Caucasian. mRNA levels of STAT4a, STAT4b, STAT1, and the type 1 IFN-induced genes PKR, MX1 and IFITM1 were assessed in peripheral blood mononuclear cells (PBMCs) from 30 pSS patients. STAT4 rs7582694 C allele was associated with pSS in both cohorts (odds ratio (OR) 1.57, 95% confidence interval (CI) 1.27-1.93, P ¼ 2.3 Â 10 À5 ). The association was increased for homozygous subjects, which suggests a recessive effect of the STAT4 at-risk allele. STAT4a, STAT4b and STAT1 mRNA levels in PBMCs were not significantly associated with rs7582694 genotypes, however the mRNA levels of STAT4a and type 1 IFN-induced genes were strongly correlated: PKR (P ¼ 4 Â 10 À3 , r ¼ 0.51), MX1 (P ¼ 2 Â 10 À4 , r ¼ 0.63) and IFITM1 (P ¼ 8 Â 10 À3 , r ¼ 0.47), suggesting that STAT4 might be involved in not only type 2 IFN production but also in type 1 IFN-mediated effects.

Non-HLA autoimmunity genetic factors contributing to Autoimmune Polyglandular Syndrome type II in Tunisian patients

“…The STAT4 gene encodes a transcription factor expressed on lymphocytes, macrophages, and dendritic cells and critical for interleukin-12 signaling, Th1 differentiation and production of interferon-c (INFc) [41]. Several investigators have confirmed associations between STAT4 variants and various AID especially with SLE [42][43][44][45]. It has also been shown that some variants of STAT4 were associated with different expression levels [46].…”

Primary Sjögren’s Syndrome: Current Pathophysiological, Diagnostic and Therapeutic Advances

“…An association between this polymorphism and high levels of IRF5 mRNA was demonstrated in PBMCs and in cultured salivary epithelial cells after viral infection ). STAT4 polymorphism was also associated with SS (Nordmark et al, 2009;Korman et al, 2008;Gestermann et al, 2010;Palomino-Morales et al, 2010). MECP2 and IL2-IL21 polymorphisms have also been associated with SS (Cobb et al, 2010;Maiti et al, 2010).…”

“…An increasing body of evidence for the implication of other gene variants outside the HLA locus association is being put forth recently. Gene polymorphisms of IRF-5 and STAT-4 genes, two transcription factors of pivotal importance in interferon pathway, have been associated with various autoimmune diseases (Martinez et al, 2008), as well as with SS Korman et al, 2008;Miceli-Richard et al, 2009;Nordmark et al, 2009, Gestermann et al, 2010. The most significantly associated single nucleotide polymorphism (SNP) of the IRF5 gene was a 4 fold repetition, instead of three, of a sequence within the promoter region (Nordmark et al, 2009).…”

Association of Stat4 Gene Single-Nucleotide Polymorphism With Systemic Lupus Erythematosus.

“…Signal transducer and activator of transcription 4 (STAT4) is a ranscription factor mainly activated by interleukin 12, which promotes the secretion of type 2 interferon (IFN) by T-helper 1 cells [7].The STAT4 gene encodes a transcription factor belonging to the STAT family expressed in lymphocytes, macrophages, and dendritic cells. STAT4 is essential for interleukin (IL)-12 signaling and induces interferon-gamma (IFNγ) production and Th1 differentiation.…”