Association of the STAT4 gene with increased susceptibility for some immune‐mediated diseases

Martínez, Alfonso; Varadé, Jezabel; Márquez, Ana; Cénit, M C; Espino, Laura; Perdigones, Nieves; Santiago, José Luis; Fernández‐Arquero, Miguel; Calle, Hermenegildo de la; Arroyo, Rafael; Mendoza, Juan L.; Fernández‐Gutiérrez, Benjamín; Concha, Emilio G. de la; Urcelay, Elena

doi:10.1002/art.23792

Cited by 120 publications

(95 citation statements)

References 41 publications

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“…STAT3 and STAT4 were shown to be constitutively activated in Crohn's patients but not in healthy volunteers. 15 STAT4 has been shown to be Association of SLE in Hong Kong Chinese W Yang et al involved in several autoimmune diseases, such as inflammatory bowel disease and type I diabetes mellitus 16 as well as Sjogren's disease 17 in addition to SLE and RA. Association of rs7574865 with SLE in multiple populations and with disease severity 5,[9][10][11] indicates that the SNP may be a functional variant itself, but this cannot be proved unless there is detailed functional characterization of the SNP or extensive in-depth sequencing in the region excluding the existence of a true functional variant in LD with rs7574865.…”

Section: Discussionmentioning

confidence: 99%

Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese

Yang

Zhao

et al. 2009

Genes Immun

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In this study, we compared the association of several newly discovered susceptibility genes for systemic lupus erythematosus (SLE) between populations of European origin and two Asian populations. Using 910 SLE patients and 1440 healthy controls from Chinese living in Hong Kong, and 278 SLE patients and 383 controls in Thailand, we studied association of STAT4, BLK and PXK with the disease. Our data confirmed association of STAT4 (rs7574865, odds ratio (OR) ¼ 1.71, P ¼ 3.55 Â 10 À23 ) and BLK (rs13277113, OR ¼ 0.77, P ¼ 1.34 Â 10 À5 ) with SLE. It was showed that rs7574865 of STAT4 is also linked to hematologic disorders and potentially some other subphenotypes of the disease. More than one genetic variant in STAT4 were found to be associated with the disease independently in our populations (rs7601754, OR ¼ 0.59, P ¼ 1.39 Â 10 À9 , and P ¼ 0.00034 when controlling the effect of rs7574865). With the same set of samples, however, our study did not detect any significant disease association for PXK, a risk factor for populations of European origin (rs6445975, joint P ¼ 0.36, OR ¼ 1.06, 95% confidence interval: 0.93-1.21). Our study indicates that some of the susceptibility genes for this disease may be population specific.

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Section: Discussionmentioning

confidence: 99%

Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese

Yang

Zhao

et al. 2009

Genes Immun

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“…36 Recently, an association between STAT4 and inflammatory bowel diseases and type I diabetes has been shown, whereas there was no association with multiple sclerosis. 35,37 A functional role is suggested for the risk haplotype of STAT4, which is tagged by the SNP rs7582694 by allele-specific differences in the expression of the risk haplotype in cells of mesenchymal origin. 16 Whereas STAT4 has been associated with rheumatic diseases in patients of Caucasian and Asian origin, polymorphisms in IRF5 have been associated with SLE in multiple ethnic populations, including Hispanics and African Americans.…”

Section: Discussionmentioning

confidence: 99%

Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome

et al. 2008

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Primary Sjö gren's syndrome (SS) shares many features with systemic lupus erythematosus (SLE). Here we investigated the association of the three major polymorphisms in IRF5 and STAT4 found to be associated with SLE, in patients from Sweden and Norway with primary SS. These polymorphisms are a 5-bp CGGGG indel in the promoter of IRF5, the single nucleotide polymorphism (SNP) rs10488631 downstream of IRF5 and the STAT4 SNP rs7582694, which tags the major risk haplotype of STAT4. We observed strong signals for association between all three polymorphisms and primary SS, with odds ratios (ORs) 41.4 and P-values o0.01. We also found a strong additive effect of the three risk alleles of IRF5 and STAT4 with an overall significance between the number of risk alleles and primary SS of P ¼ 2.5 Â 10 À9 . The OR for primary SS increased in an additive manner, with an average increase in OR of 1.78. For carriers of two risk alleles, the OR for primary SS is 1.43, whereas carriers of five risk alleles have an OR of 6.78. IRF5 and STAT4 are components of the type I IFN system, and our findings emphasize the importance of this system in the etiopathogenesis of primary SS.

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“…Moreover, the MST1R-deficient mouse showed a more rapid onset after EAE (experimental autoimmune encephalitis) induction with overall worsened severity, together with exacerbated demyelization, axonal injury and neuroinflammation. 10 Genetic risk factors are sometimes shared by multiple diseases (the PTPN22 C1858T allele or the STAT4 gene 11,12 ). Imputation from the Wellcome Trust Case Control Consortium data 1 allows discarding a similar role of the BSN polymorphism rs9858542 originally found associated with CD in other autoimmune complex diseases, like rheumatoid arthritis or type I diabetes.…”

Section: Introductionmentioning

confidence: 99%

Effect of BSN-MST1 locus on inflammatory bowel disease and multiple sclerosis susceptibility

et al. 2009

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Genome-wide studies highlighted the effect in Crohn's disease (CD) and ulcerative colitis (UC) susceptibility of single nucleotide polymorphisms (SNPs) in 3p21, where BSN (bassoon), MST1 (macrophage stimulating-1) and MST1R (MST1 Receptor) genes map. MST1R expression was significantly downregulated in multiple sclerosis (MS) compared with control brains, resembling findings in the MS mouse model. We pursued to replicate the effect of this locus on inflammatory bowel diseases and to evaluate its contribution to MS risk. Polymorphisms rs9858542, rs2131109 and rs1128535 were analysed by TaqMan assays in Spanish patients (370 CD, 405 UC and 415 MS) and 800 ethnically matched controls. Allele frequencies of these SNPs were significantly different in CD patients compared with controls [rs9858542: P ¼ 0.001, Odds ratio (OR) ¼ 1.35; rs2131109: P ¼ 0.0005, OR ¼ 1.37; rs1128535: P ¼ 0.007, OR ¼ 0.78] and, specifically, in the ileal phenotype [rs9858542: P ¼ 0.0004, OR ¼ 1.47; rs2131109: P ¼ 0.00009, OR ¼ 1.52; rs1128535: P ¼ 0.02, OR ¼ 0.69]. No differences were detected between UC or MS patients and control individuals. The effect of this locus on CD predisposition was replicated, but no influence on UC or MS predisposition could be detected. This susceptibility locus seems to affect mainly to the ileal CD subphenotype, although this point awaits further corroboration in independent cohorts.

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Association of the STAT4 gene with increased susceptibility for some immune‐mediated diseases

Cited by 120 publications

References 41 publications

Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese

Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese

Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome

Effect of BSN-MST1 locus on inflammatory bowel disease and multiple sclerosis susceptibility

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