This meta-analysis demonstrates that the STAT4rs7574865 T allele confers susceptibility to SLE, RA, T1D, SSc, JIA, APS, IBD-UC, and pSS patients, supporting the hypothesis of association between STAT4 gene polymorphism and subgroup of autoimmune diseases.
Taking into consideration that the different autoimmune diseases may share some common pathogenetic pathways, the aim of the present study was to evaluate the role of STAT4rs7574865 polymorphism on acute allograft rejection.
This is the first study to show a positive association between a STAT4 polymorphism and type-1 autoimmune hepatitis, suggesting that autoimmune hepatitis shares a gene commonly associated with risk for other autoimmune diseases.
Among these autoimmunity risk genes are IFN regulatory factor 5 (IRF5), which is involved in TLR signaling, and the signal transducer and activator of transcription 4 (STAT4) that interacts with the type I IFN receptor.
Taken together, these results suggest that STAT4 polymorphisms are associated with autoimmune diseases which are characterized by a systemic pathology and anti-dsDNA antibody.
The signal transducer and activator of transcription 4 (STAT4) gene is one of the most interesting genes for the pathogenesis of autoimmune diseases, including T1D.
As the TT genotype is associated with autoimmune diseases, our results seem at a paradox with current evidence hinting at a different role of STAT4 in normal circumstances versus immunocompromised patients.
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.
We tested the high a priori possibility that well-established non-HLA autoimmunity loci were involved in APSII and confirmed five association signals to APSII, namely: (1) two T1D-associated SNPs, in CTLA4 and IL2RA, suggest their involvement in T1D pathogenesis in this cohort; (2) two SNPs in STAT4 and IL15 not previously associated to endocrinopathies, are possibly involved in co-occurrence of organ autoimmunity in APSII, and; (3) one SNP in TNF alpha showed association to APSII irrespective of AD.
But, no significant differences in allele and genotype frequencies of STAT4rs7574865 polymorphism were detected according to the presence of another autoimmune disease, nodules and in HLA-DRB1*04 and HLA-DRB1*0404 positive subgroups.
We found that mutated allele T of the STAT4rs7574865 SNP, which previously was implicated in the predisposition to many autoimmune diseases, were more common in individuals with psoriasis than in controls (p = 0.045, odds ratio = 1.42, 95% confidence interval 1.01-2.00), thus concluding that the polymorphism examined is associated with the development of psoriasis in our population.
Our data strengthen STAT4rs7574865 polymorphism as a susceptibility factor for RA and SLE and provide further evidence for a common origin of autoimmune diseases.
We recently reported for the first time as a PS-associated SNP the signal transducer and activator of transcription-4 (STAT4) rs7574865 polymorphism, which is also associated with several autoimmune diseases.
In concert with the identification of other disease-associated loci, elucidating how the variant form of STAT4 modulates immune function should lead to an improved understanding of the pathophysiology of autoimmunity.
Our data demonstrated that the STAT4 genetic variants could predispose an individual to IBD and its extra-intestinal ailments in Koreans, suggesting the common pathogenesis of IBD (especially, extra-intestinal manifestations) and other autoimmune diseases.
These findings suggest that this variant form of STAT4 may have a putative key role in the development of a variety of autoimmune diseases, probably because of signaling defects that it causes in the IL-12 pathway.