STAT4 rs7574865 G/T and PTPN22 rs2488457 G/C Polymorphisms Influence the Risk of Developing Juvenile Idiopathic Arthritis in Han Chinese Patients

Zhang, Fan; Wang, Feifei; Huang, Hui; Huang, Na; Ma, Huihui; Guo, Yanjie; Zhang, Yayuan; Qian, Xiaohong; Yu, Haiguo

doi:10.1371/journal.pone.0117389

Cited by 19 publications

(14 citation statements)

References 27 publications

(47 reference statements)

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“…Patients with an abnormally low level of STAT2 expression are susceptible to virus infections (Shahni et al 2015) but, very surprisingly, the complete loss of STAT2 expression does not seem to eliminate completely the host defense against many viruses, but does sensitize affected individuals to measles (Hambleton et al 2013). For STAT4, some polymorphisms influence the risk of developing juvenile arthritis (Fan et al 2015).…”

Section: The Gain-of-function Stat1 Paradox In Infectious Diseasementioning

confidence: 99%

Responses to Cytokines and Interferons that Depend upon JAKs and STATs

Stark

Cheon

Wang

2017

Cold Spring Harb Perspect Biol

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Many cytokines and all interferons activate members of a small family of kinases (the Janus kinases [JAKs]) and a slightly larger family of transcription factors (the signal transducers and activators of transcription [STATs]), which are essential components of pathways that induce the expression of specific sets of genes in susceptible cells. JAK-STAT pathways are required for many innate and acquired immune responses, and the activities of these pathways must be finely regulated to avoid major immune dysfunctions. Regulation is achieved through mechanisms that include the activation or induction of potent negative regulatory proteins, posttranslational modification of the STATs, and other modulatory effects that are cell-type specific. Mutations of JAKs and STATs can result in gains or losses of function and can predispose affected individuals to autoimmune disease, susceptibility to a variety of infections, or cancer. Here we review recent developments in the biochemistry, genetics, and biology of JAKs and STATs. Because the basic biochemistry of Janus kinase -signal transducers and activators of transcription (JAK-STAT) signaling pathways has been frequently and extensively reviewed (see, for example, Stark and Darnell 2012;Cai et al. 2015;O'Shea et al. 2015;Villarino et al. 2015), we present here only a brief summary. After a cytokine or interferon binds to its specific receptor, the receptor forms homodimers, heterodimers, or trimers, depending on the cytokine, thus activating the tightly bound JAKs to cross-phosphorylate each other. The activated JAKs then phosphorylate specific tyrosine residues in the cytoplasmic domains of the receptors, providing binding sites for the STATs through their highly conserved SH2 domains. The receptor-bound STATs are phosphorylated, each on a highly conserved tyrosine residue, after which they leave the receptor as homo-or heterodimers whose association is strengthened by SH2-phosphotyrosine interactions. The phosphorylated STAT dimers are then transported to the nucleus, where they bind to and activate specific promoters. The basic outline of JAK-STAT signaling (Fig. 1) shows that interferon (IFN)-g (type II IFN) and all of the cytokines primarily drive the formation of specific STAT homodimers, which then bind to DNA directly. However, in some cases, heterodimers involving STAT1 and STAT3 or STAT5A and STAT5B can also form. In contrast, IFN-b and the subtypes of IFN-a (collectively type I IFNs) and the subtypes of IFN-l (collectively type III IFNs) drive the formation of STAT1-STAT2 heterodimers, which then associate with the DNA-binding interferon regulatory protein 9 (IRF9) to form in-

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Section: The Gain-of-function Stat1 Paradox In Infectious Diseasementioning

confidence: 99%

Responses to Cytokines and Interferons that Depend upon JAKs and STATs

Stark

Cheon

Wang

2017

Cold Spring Harb Perspect Biol

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“…Several SNPs in the gene have been significantly association with Behcet's Disease [119], diabetes risk [107], hepatitis B virus-related hepatocellular carcinoma [107,111,120,121], inflammatory bowel disease [122], juvenile idiopathic arthritis [123], primary biliary cirrhosis and Crohn's disease [124], severe renal insufficiency in lupus nephritis [109], systemic lupus erythematosus [106] and ulcerative colitis [125]. Some STAT4 SNPs were found to create alterations in punitive TFBS and these punitive changes were examined with respect to these disease or conditions [25].…”

Section: Signal Transducer and Activator Of Transcription 4 (Stat4)mentioning

confidence: 99%

“…The rs7574865 STAT4 SNP (G/T) has been found to be significantly associated with diabetes [112], hepatitis B virus-related hepatocellular carcinoma [107,111,120,121], inflammatory bowel disease [122], juvenile idiopathic arthritis [123], primary biliary cirrhosis and Crohn's disease [124], severe renal insufficiency in lupus nephritis [109], systemic lupus erythematosus [106] and ulcerative colitis [125]. The minor T-allele for the SNP creates a unique punitive TFBS not found with the common G-allele for the nuclear receptor subfamily 1, group H, member 3: retinoid X receptor, alpha (NR1HE:RXRα TF which is a key regulator of macrophage function, controlling transcriptional programs involved in lipid homeostasis and inflammation [25].…”

Section: Signal Transducer and Activator Of Transcription 4 (Stat4)mentioning

confidence: 99%

SNPs, transcriptional factor binding sites and disease

Buroker¹

2017

Biomed Genet Genomics

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“…The coding region consists of 22 exons with a large 70 kb intron between exons 2 and 3. Several SNPs in the gene have been significantly association with Behcet's Disease [18], diabetes risk [11], hepatitis B virus-related hepatocellular carcinoma [6,10,19,20], inflammatory bowel disease [21], juvenile idiopathic arthritis [22], primary biliary cirrhosis and Crohn's disease [23], severe renal insufficiency in lupus nephritis [8], systemic lupus erythematosus [5] and ulcerative colitis [24] ( Table 1).…”

Section: Introductionmentioning

confidence: 99%

“…The rs7574865 STAT4 SNP has been found to be significantly associated with diabetes [11], hepatitis B virus-related hepatocellular carcinoma [6,10,19,20], inflammatory bowel disease [21], juvenile idiopathic arthritis [22], primary biliary cirrhosis and Crohn's disease [23], severe renal insufficiency in lupus nephritis [8], systemic lupus erythematosus [5] and ulcerative colitis [24]. The rs11889341 STAT4 SNP has been found to be significantly associated with diabetes [11], hepatitis B virus (HBV) infection, HBV-related cirrgisus and hepatocellular carcinoma [23], severe renal insufficiency in lupus nephritis [8], and systemic lupus erythematosus [5].…”

Section: Introductionmentioning

confidence: 99%

Computational STAT4 rSNP Analysis, Transcriptional Factor Binding Sites And Disease

Buroker

2016

JBD

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Purpose -Signal Transducer and Activator of Transcription 4 (STAT4) is important for signaling by interleukins and type 1 interferons and has been found to have several simple nucleotide polymorphisms (SNPs) associated with human disease. STAT4 SNPs were computationally examined with respect to changes in potential transcriptional factor binding sites (TFBS) and these changes were discussed in relation to human disease. Methods -The JASPAR CORE and ConSite databases were instrumental in identifying the TFBS. TheVector NTI Advance 11.5 computer program was employed in locating all the TFBS in the STAT4 gene from 4 kb upstream of the transcriptional start site to 8.3 kb past the 3'UTR. The JASPAR CORE database was also involved in computing each nucleotide occurrence (%) within the TFBS.Results -The STAT4 SNPs in the 70 kb intron between exon 2 and 3 are in linkage disequilibrium and have previously been found to be significantly associated with several vasculitis diseases as well as diabetes. The SNP alleles were found to alter the DNA landscape for potential transcriptional factors (TFs) to attach resulting in changes in TFBS and thereby, alter which transcriptional factors potentially regulate the STAT4 gene. These STAT4 SNPs should be considered as regulatory (r) SNPs.Conclusion -The alleles of each rSNP were found to generate unique TFBS resulting in potential changes in TF STAT4 regulation. These regulatory changes were discussed with respect to changes in human health that result in disease.

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STAT4 rs7574865 G/T and PTPN22 rs2488457 G/C Polymorphisms Influence the Risk of Developing Juvenile Idiopathic Arthritis in Han Chinese Patients

Cited by 19 publications

References 27 publications

Responses to Cytokines and Interferons that Depend upon JAKs and STATs

Responses to Cytokines and Interferons that Depend upon JAKs and STATs

SNPs, transcriptional factor binding sites and disease

Computational STAT4 rSNP Analysis, Transcriptional Factor Binding Sites And Disease

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