Associations between NOD2, IRGM and ORMDL3 polymorphisms and pediatric-onset inflammatory bowel disease in the Lithuanian population

Pranculienė, Gitana; Steponaitienė, Rūta; Skiecevičienė, Jurgita; Kučinskienė, Rūta; Kiudelis, Gediminas; Adamonis, Kęstutis; Labanauskas, Liutauras; Kupčinskas, Limas

doi:10.1016/j.medici.2016.11.006

Cited by 14 publications

(13 citation statements)

References 28 publications

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“…We know that in the IL-10 pathway, upon binding of IL-10 to cell receptors IL10RA and IL10RB, the IL-10 receptor complex members JAK1 and Tyk2 are activated and catalyze phosphorylation of themselves and then of IL10RA[3,4], thereby forming a docking site for STAT3. STAT3 is phosphorylated by JAK1 and Tyk2, and this phosphorylation causes STAT3 dimerization and translocation to the nucleus where it can induce expression of its target genes including HO-1 .…”

Section: Discussionmentioning

confidence: 99%

“…A genome-wide association study (GWAS) in the Polish population revealed that the genetic architecture is different between pediatric and adult-onset IBD[2]. Adult IBD-associated genes NOD2 (Leu1007insC) and IRGM have been shown to be associated with increased risk of Crohn’s disease (CD) and ORMDL3 variant with susceptibility to ulcerative colitis (UC) in Lithuanian early-onset IBD patients[3]. The TRIM22-NOD2 network, signaling pathways and genetic factors are associated with very early-onset (VEO) and adult IBD.…”

Section: Introductionmentioning

confidence: 99%

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Genetic association and epistatic interaction of the interleukin-10 signaling pathway in pediatric inflammatory bowel disease

Lin

Wang

Hegarty

et al. 2017

WJG

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AIMTo study the genetic association and epistatic interaction of the interleukin (IL)-10 and IL-10/STAT3 pathways in pediatric inflammatory bowel disease (IBD).METHODSA total of 159 pediatric inflammatory IBD patients (Crohn’s disease, n = 136; ulcerative colitis, n = 23) and 129 matched controls were studied for genetic association of selected single nucleotide polymorphisms (SNPs) of the IL-10 gene and the genes IL10RA, IL10RB, STAT3, and HO1, from the IL-10/STAT3 signaling pathway. As interactions between SNPs from different loci may significantly affect the associated risk for disease, additive (a) and dominant (d) modeling of SNP interactions was also performed to examine high-order epistasis between combinations of the individual SNPs.RESULTSThe results showed that IL-10 rs304496 was associated with pediatric IBD (P = 0.022), but no association was found for two other IL-10 SNPs, rs1800872 and rs2034498, or for SNPs in genes IL10RA, IL10RB, STAT3, and HO1. However, analysis of epistatic interaction among these genes showed significant interactions: (1) between two IL-10 SNPs rs1800872 and rs3024496 (additive-additive P = 0.00015, Bonferroni P value (Bp) = 0.003); (2) between IL-10RB rs2834167 and HO1 rs2071746 (dominant-additive, P = 0.0018, Bp = 0.039); and (3) among IL-10 rs1800872, IL10RB rs2834167, and HO1 rs2071746 (additive-dominant-additive, P = 0.00015, Bp = 0.005), as well as weak interactions among IL-10 rs1800872, IL-10 rs3024496, and IL-10RA (additive-additive-additive, P = 0.003; Bp = 0.099), and among IL10RA, IL10RB, and HO1 genes (additive-dominant-additive, P = 0.008, Bp = 0.287).CONCLUSIONThese results indicate that both the IL-10 gene itself, and through epistatic interaction with genes within the IL-10/STAT3 signaling pathway, contribute to the risk of pediatric IBD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic association and epistatic interaction of the interleukin-10 signaling pathway in pediatric inflammatory bowel disease

Lin

Wang

Hegarty

et al. 2017

WJG

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“…Today more than 60 polymorphisms of this gene have been identified; however, three common mutations Leu1007fsinsC, Arg702Trp, and Gly908Arg have been specifically associated with ileal involvement, stricturing complications, and earlier age of onset [18].…”

Section: Single-nucleotide Polymorphisms In Innate and Adaptive Immunmentioning

confidence: 99%

Single-Nucleotide Polymorphisms in Inflammatory Bowel Disease

Dudzińska¹

2020

The Recent Topics in Genetic Polymorphisms

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Inflammatory bowel disease (IBD) mainly includes ulcerative colitis (UC) and Crohn's disease (CD). Both conditions are characterized by chronic inflammation of the gastrointestinal tract, with alternating periods of relapse and remission. Both forms of IBD involve an uncontrolled inflammatory process in the intestines, leading to worsening quality of life and requiring long-term medical and/or surgical intervention. Epidemiological and clinical studies suggest that the pathogenesis of inflammatory bowel disease is strongly linked to genetic predisposition. CD and UC are considered polygenic diseases in which familial clustering is observed in 5-10% of patients. Among genetic factors associated with IBD development, it has been found that many single nucleotide polymorphisms are associated with susceptibility to IBD progression. SNP can affect the production or function of a protein and thus affect the development of the disease. However, although the overall role of genes involved in the development of IBD is already in most cases known, as of today it is unclear how the SNPs in these genes affect cellular function, or how such changed cellular functions would contribute to the development of IBD. In the present work several selected polymorphisms in genes involved in IBD development are discussed.

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“…Several susceptibility loci encode proteins with important roles in proteostasis. Three ER relevant genes are identified that include Orosmucoid-like 3 (ORMDL3) [13,14], anterior gradient 2 (AGR2) [15,16], and XBP1 [17]. ORMDL3 is a key UPR inducer by affecting calcium homeostasis in the ER and a risk locus for both Crohn's disease and ulcerative colitis [18,19].…”

Section: Upr and Ibdmentioning

confidence: 99%

Unfolded Protein Response and Crohn’s Diseases: A Molecular Mechanism of Wound Healing in the Gut

Li¹

2020

Preprint

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Endoplasmic reticulum (ER) stress triggers a series of signaling and transcriptional events termed the unfolded protein response (UPR). Severe ER stress is associated with the development of fibrosis in different organs including lung, liver, kidney, heart, and intestine. ER stress is an essential response of epithelial and immune cells in the pathogenesis of inflammatory bowel disease (IBD) including Crohn’s disease. Intestinal epithelial cells are susceptible to ER stress-mediated damage due to secretion of a large amount of proteins that are involved in mucosal defense. In other cells, ER stress is linked to myofibroblast activation, extracellular matrix production, macrophage polarization, and immune cell differentiation. This review focuses on the role of UPR in the pathogenesis in IBD from immunologic perspective. The roles of macrophage and mesenchymal cells in the UPR from in vitro and in vivo animal models are discussed. The links between ER stress and other signaling pathways such as senescence and autophagy are introduced. Recent advances in the understanding of the epigenetic regulation of UPR signaling are reported. The future directions of the development of the UPR research and therapeutic strategies to manipulate ER stress levels are also reviewed.

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Associations between NOD2, IRGM and ORMDL3 polymorphisms and pediatric-onset inflammatory bowel disease in the Lithuanian population

Cited by 14 publications

References 28 publications

Genetic association and epistatic interaction of the interleukin-10 signaling pathway in pediatric inflammatory bowel disease

Genetic association and epistatic interaction of the interleukin-10 signaling pathway in pediatric inflammatory bowel disease

Single-Nucleotide Polymorphisms in Inflammatory Bowel Disease

Unfolded Protein Response and Crohn’s Diseases: A Molecular Mechanism of Wound Healing in the Gut

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