Moreover, macrophages in synovial tissue obtained from patients with rheumatoid arthritis express Stat4 in vivo, suggesting a potential role in a prototypical Th1-mediated human disease.
However, genomic DNA isolated from 91 patients with asthma or rheumatoid arthritis showed no evidence of mutations in the defined STAT4 essential promoter region.
Unlike several other risk genes for RA such as PTPN22, PADI4, and FCRL3, a haplotype of the STAT4 gene shows consistent association with RA susceptibility across Whites and Asians, suggesting that this risk haplotype predates the divergence of the major racial groups.
Similarly, mutated allele T or genotypes T/T and G/T of the STAT4rs7574865 SNP were also associated with susceptibility to RA (OR=1.9, 95% CI=1.46-2.50, and OR=2.37, 95% CI 1.73-2.25, respectively).
Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility.
Our data strengthen STAT4rs7574865 polymorphism as a susceptibility factor for RA and SLE and provide further evidence for a common origin of autoimmune diseases.
To test the hypothesis that the variant haplotype of STAT4 seen in RA and SLE is also associated with pSS, we genotyped rs7574865, the most strongly disease-associated SNP in the variant STAT4 haplotype, in 124 Caucasian pSS subjects and compared them to 1143 Caucasian controls.
STAT4, a transcription factor transmitting signals induced by several key cytokines, has recently been identified as a genetic risk factor for rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren's disease (SD), thus indicating that multiple autoimmune diseases may share common biochemical pathways that lead to immune deregulation.
The association of STAT4 polymorphism rs7574865 with RA was validated in patients of Spanish origin (for T versus G, P = 1.2 x 10(-6), odds ratio [OR] 1.59, 95% confidence interval [95% CI] 1.31-1.92), and the association was described for the first time in both clinical forms of inflammatory bowel disease, Crohn's disease and ulcerative colitis (for T versus G, P = 0.006, OR 1.29, 95% CI 1.07-1.55), and in type 1 diabetes mellitus (for T versus G, P = 0.008, OR 1.36, 95% CI 1.07-1.71).
Our findings indicate an association between the STAT4 polymorphism rs7574865 and RA in 3 different populations, from Spain, Sweden, and The Netherlands, thereby confirming previous data.
A haplotype in STAT4 gene associated with rheumatoid arthritis in Caucasians is not associated in the Han Chinese population, but with the presence of rheumatoid factor.
Our results replicate and firmly establish the association of STAT4 and CTLA4 with RA and provide highly suggestive evidence for IL2/IL21 loci as a risk factor for RA.
Taking into consideration that different autoimmune diseases may share some common pathogenetic pathways, we hypothesized that STAT4, a susceptibility gene found to be associated with increased risk for systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, Sjögren's syndrome, Wegener's granulomatosis, Crohn's disease, and ulcerative colitis may also have a role in psoriasis.
We have demonstrated associations between JIA and variants in the TNFAIP3, STAT4, and C12orf30 regions that have previously shown associations with other autoimmune diseases, including RA and systemic lupus erythematosus.
STAT4 is a transcription factor that is activated by IFN-alpha signaling, and genetic variation of STAT4 has been associated with risk of SLE and rheumatoid arthritis.
Recent studies demonstrated an association of STAT4 variants with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), indicating that multiple autoimmune diseases share common susceptibility genes.