Evidence for STAT4 as a Common Autoimmune Gene: rs7574865 Is Associated with Colonic Crohn's Disease and Early Disease Onset

Abstract

BackgroundRecent 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. We therefore investigated the influence of STAT4 variants on the susceptibility and phenotype of inflammatory bowel diseases (IBD) in a large patient and control cohort.Methodology/Principal FindingsGenomic DNA from 2704 individuals of Caucasian origin including 857 patients with Crohn's disease (CD), 464 patients with ulcerative colitis (UC), and 1383 healthy, unrelated controls was analyzed for seven SNPs in the STAT4 gene (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694, rs10174238). In addition, a detailed genotype-phenotype analysis was performed. Our analysis revealed an association of the STAT4 SNP rs7574865 with overall decreased susceptibility to CD (p = 0.047, OR 0.86 [95% CI 0.74–0.99]). However, compared to CD patients carrying the wild type genotype, the STAT4 SNP rs7574865 was significantly associated with early CD onset (p = 0.021) and colonic CD (p = 0.008; OR = 4.60, 95% CI 1.63–12.96). For two other STAT4 variants, there was a trend towards protection against CD susceptibility (rs7568275, p = 0.058, OR 0.86 [95% CI 0.74–1.00]; rs10174238, p = 0.057, OR 0.86 [95% CI 0.75–1.00]). In contrast, we did not observe any association with UC susceptibility. Evidence for weak gene-gene interaction of STAT4 with the IL23R SNP rs11209026 was lost after Bonferroni correction.Conclusions/SignificanceOur results identified the STAT4 SNP rs7574865 as a disease-modifying gene variant in colonic CD. However, in contrast to SLE and RA, the effect of rs7574865 on CD susceptibility is only weak.

Biomarkers in the Management of Scleroderma: An Update

“…One such study, conducted on more than 2,000 patients and replicated in a second cohort of almost 3,000 patients, identified as the strongest susceptibility locus (besides the HLA region) an SNP in the CD247 gene and confirmed the previously known association with STAT4 and IRF5 gene polymorphisms [11••]. Although they are potentially very interesting for gaining insight into the pathogenesis of SSc, genetic associations in the same loci have been found in other conditions, such as systemic lupus erythematosus (SLE) [12,13] and rheumatoid arthritis [14]. Therefore, detailed comparative studies are needed to assess their specificity for SSc.…”

A single-nucleotide polymorphism of the STAT4 gene is associated with systemic lupus erythematosus (SLE) in female Chinese population

“…Accordingly, patients with SLE show up-regulation of the type 1 IFN system [8]. Apart from this, STAT4 has also been reported to be associated with many other autoimmune diseases, such as rheumatoid arthritis, Crohn's disease, asthma, systemic sclerosis, and Sjögren's syndrome [9][10][11][12][13]. In the genetic analysis of SLE susceptibility, several genome-wide association studies (GWAS) have identified STAT4 as a susceptible gene.…”

Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis

“…Recently, STAT4 haplotype characterized by the rs7574865 polymorphism was reported to be significantly associated with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and other autoimmune diseases such as Sjögren's syndrome, type 1 diabetes, and systemic sclerosis [16][17][18]. Interestingly, a recent casecontrol study conducted in a Spanish population showed that the T allele of the STAT4 rs7574865 was associated with IBD [19], and this association has been replicated by Diaz-Gallo et al [20] and Glas et al [21], they reported that rs7574865 polymorphism was associated with colonic CD and early disease onset in Caucasians. However, there are also some other studies did not confirm these findings.…”