Association of STAT4 rs7574865 polymorphism with autoimmune diseases: a meta-analysis

Abstract

The association between the signal transducer and activator of transcription 4 (STAT4) gene rs7574865 single nucleotide polymorphism and different autoimmune diseases remains controversial and ambiguous. We conducted this study to investigate whether combined evidence shows the association between STAT4 rs7574865 polymorphism and autoimmune diseases. Comprehensive Medline search and review of the references were used to get the relevant reports published before September 2011. Meta-analysis was conducted for genotype T/T (recessive effect), T/T + G/T (dominant effect) and T allele in random effects models. 40 studies with 90 comparisons including 32 systemic lupus erythematosus (SLE), 19 rheumatoid arthritis (RA), 3 type 1 diabetes (T1D), 11 Systemeric Sclerosis (SSc), 4 inflammatory bowed diseases (IBD), 3 Primary Sjogren's syndrome (pSS), 4 juvenile idiopathic arthritis (JIA), 2 Primary antiphospholipid syndrome (APS), 1 Autoimmune thyroid diseases, 1 multiple sclerosis, 1 Psoriasis, 1 Wegener's granulomatosis, 1 Type 2 diabetes, and 1 giant cell arteritis disease were available for this meta-analysis. The overall odds ratios for rs7574865 T-allele significantly increased in SLE, RA, T1D, SSc, JIA, and APS (OR = 1.56, 1.25, 1.13, 1.34, 1.25, and 2.15, respectively, P < 0.00001) and in IBD-UC and pSS (OR = 1.11 and 1.33, respectively, P < 0.05). This meta-analysis demonstrates that the STAT4 rs7574865 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.

Meta-analysis of STAT4 and IFIH1 polymorphisms in type 1 diabetes mellitus patients with autoimmune polyglandular syndrome type III

“…The rs7574865 SNP is one of the most frequently examined polymorphisms in the STAT4 gene and its function is related to gene expression on a transcriptional level and splice variation (Liang et al, 2012). The T allele of this particular SNP has been associated with multiple autoimmune disorders but the association is dependent on the population examined (Lee et al, 2010).…”

“…Furthermore, patients with APSIII may also be diagnosed with celiac disease (CD). Despite the genetic variation in human leukocyte antigen (HLA) and its involvement in T1D development, new genes have been identified as potentially important in disease's susceptibility and modulation outside HLA range (Gillespie, 2006;Liang et al, 2012).…”

“…Since Th1 cells are critical effectors of chronic inflammation disorders, STAT4 could play a pivotal role in the pathogenesis of immune diseases (Kobayashi et al, 2008;Zervou et al, 2008;Bi et al, 2013;Zheng et al, 2013). In fact, single nucleotide polymorphisms (SNPs) within STAT4 (chromosome location: 2q32.2-q32.3) have been reported to be associated with increased risk for several autoimmune diseases (Liang et al, 2012), including rheumatoid arthritis (RA) (Stark et al, 2009), systemic lupus erythematosus (SLE) (Kobayashi et al, 2008), and Sjögren's syndrome (SS) (Palomino-Morales et al, 2010). Viral infections have been implicated as triggers in autoimmune disorders in T1D (Jun and Yoon, 2001;Salminen et al, 2003).…”

STAT4 is required for IL-23 responsiveness in Th17 memory cells and NKT cells

“…4,22 Genome-wide association studies have implicated STAT4 in diseases such as asthma, IBD, RA and SLE [23][24][25] and IL23R in IBD, psoriasis and RA. [26][27][28][29] Our data provide a link between a T cell-extrinsic role for STAT4 in mediating IL-23 responsiveness to memory T helper and NKT cells, and IL-17 production.…”

Association of STAT4 gene single nucleotide polymorphisms with Iranian juvenile-onset systemic lupus erythematosus patients

“…The rs7574865 G/T SNP occurs in intron 3 of STAT4 gene, and has been associated with juvenile idiopathic arthritis (JIA) in non-Hispanic white population 5 . Genome-wide association study (GWAS) and a meta-analysis have reported that STAT4 rs7574865 T allele confers susceptibility to JIA, SLE, rheumatoid arthritis (RA), type 1 diabetes (T1D), systemic sclerosis (SSc), primary antiphospholipid syndrome (APS), inflammatory bowel diseases-ulcerative colitis (IBD-UC), and primary Sjogren's syndrome (pSS) 6,7 . Moreover, the minor C allele of STAT4 rs7601754 SNP was shown to be a protective allele in SLE, whereas the major T allele might be a risk allele for SLE susceptibility 8 .…”