<i>STAT3</i> Genotypic Variant <i>rs744166</i> and Increased Tyrosine Phosphorylation of STAT3 in IL-23 Responsive Innate Lymphoid Cells during Pathogenesis of Crohn's Disease.
In addition, IL-10-mediated suppression of TNFα production upon LPS stimulation and IL-10-induced STAT3 phosphorylation were attenuated in patients with CD versus controls.
Logistic regression model was used to examine the association between single nucleotide polymorphism (SNP) of STAT3 and CD risk; the odds ratio (OR) and 95 % confident interval (95 % CI) were calculated.
This is the first study of the single marker association of IL23R, JAK2, and STAT3 polymorphisms with ulcerative colitis and Crohn's disease in a Turkish population.
We observed a unique phospho-STAT3(S727) response in patients with Montreal B2 Crohn's disease, particularly in response to IL-6 leading to increased TGF-β1, collagen, and CTGF production in ileal strictures.
Additional suggestive associations (P < 4.2 × 10(-5)) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 and near LINC00994.
The results indicated that the STAT3rs744166 polymorphism was associated with CD and UC susceptibility (CD: GA+AA vs. GG, OR = 1.20, 95%CI, 1.11-1.30, I2 = 0%, Punadjusted<0.00001, PBonferroni<0.00005, PFDR<0.00001; UC: GA+AA vs. GG, OR = 1.21, 95%CI, 1.08-1.36, I2 = 1%, Punadjusted = 0.001, PBonferroni = 0.005, PFDR = 0.00125).
Elevated plasma IL-6 levels were detected in CD (P = 0.004), which strongly correlated with disease activity (ρ = 0.690, P<0.001) but not with IL-6-induced STAT3 phosphorylation.
IL-6/STAT3/SOCS3 signaling pathway plays an important role in the pathogenesis of Crohn's disease by induction of the antiapoptotic factors Bcl-2 and Bcl-xl in lamina propria mononuclear cells (LPMCs).
We confirmed associations of Crohn's disease with variants in MHC (rs7765379, P = 2.11 × 10(-59)), TNFSF15 (rs6478106, P = 3.87 × 10(-45)), and STAT3 (rs9891119, P = 2.24 × 10(-14)).
Our data confirm the association between JAK2 rs10758669 (p = 0.026, OR = 1.25, 95% CI = 1.04-1.50) and STAT3rs744166 (p = 0.04, OR = 0.83, 95% CI = 0.688-0.998) with CD, but not UC.
Colonic expression of genes regulating STAT3 signaling and leukocyte recruitment and function was measured in pediatric patients with Crohn disease (CD) stratified by STAT3 genotype.
Data on genetic interaction reveals that the above JAK2 and STAT3 risk alleles contribute to CD susceptibility in combination with each other (OR: 2.218; 95% CI: 1.097-4.487; P = 0.024), while the JAK2 variant shows a tendency to confer UC risk only on a wild-type STAT3 background (OR: 1.997, 95%CI: 0.994-4.009, P = 0.049).
DNA was tested for three CD-associated NOD2 variants (3020insC, G908R, R702W), variants in IRGM, ATG16L1, IL12B, IL23R, STAT3, and a TLR5-stop mutation.
Other than genetic variants of IL-10 receptors, IL-10 and STAT3 genes are also associated with IBD, emphasizing the involvement of the IL-10 signalling cascade in the pathogenesis of CD and UC.
We recruited 369 AJ CD patients and 503 AJ controls, genotyped 22 single nucleotide polymorphisms (SNPs) at or near 10 CD-associated genes, NOD2, IL23R, IRGM, ATG16L1, PTGER4, NKX2-3, IL12B, PTPN2, TNFSF15 and STAT3, and assessed their association with CD status.
The originally described association of IBD with STAT3 polymorphisms is corroborated for the two clinical phenotypes, CD and UC, in an independent population.