Ignite Creation Date:
2024-05-06 @ 2:20 PM
Last Modification Date:
2024-10-26 @ 1:29 PM
Study NCT ID:
NCT04284878
Status:
UNKNOWN
Last Update Posted:
2020-02-26
First Post:
2020-02-23
Brief Title:
Lymphoid Tyrosine Phosphatase Gene Polymorphisms in Inflammatory Bowel Disease
Sponsor:
Assiut University
Organization:
Assiut University
Study Overview
Official Title:
Lymphoid Tyrosine Phosphatase Gene Polymorphisms in Inflammatory Bowel Disease
Status:
UNKNOWN
Status Verified Date:
2020-02
Last Known Status:
NOT_YET_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This study aims
1 To investigate the association between single nucleotide polymorphisms of PTPN22 gene rs2476601 rs33996649 and rs2488457 and inflammatory bowel disease
2 To correlate the relation between the studied SNPs and disease activity response to therapy
1 To investigate the association between single nucleotide polymorphisms of PTPN22 gene rs2476601 rs33996649 and rs2488457 and inflammatory bowel disease
2 To correlate the relation between the studied SNPs and disease activity response to therapy
Detailed Description:
The inflammatory bowel diseases IBD are chronic inflammatory disorders of the gastrointestinal tract that manifests as Crohns disease CD and Ulcerative colitis UC clinically characterized by periods of remission interrupted by episodes of clinical disease activity Zallot et al 2013 Patients with IBD display some common symptoms such as severe diarrhea pain fatigue and weight loss but the localization is slightly different whereas CD affects the whole gastrointestinal tract UC primarily affects the distal intestine and ileum De Lange et al 2015
Lennard-Jones et al have defined macroscopic and microscopic criteria to establish the diagnosis of Crohns disease The macroscopic diagnostic tools include physical examination endoscopy and radiology Microscopic features can be assessed on mucosal biopsy andor operative specimen The diagnosis depends on the finding of discontinuous and often granulomatous intestinal inflammation Lennard-Jones et al 1997 Diagnosis of ulcerative colitis is based on history endoscopic appearances histopathology of multiple mucosal biopsies and appropriate radiology Silverberg et al 2005 Satsangi et al 2006
The incidence pattern of UC has changed over the last two decades with incidence continuing to rise in the West and rising incidence in previously low incidence areas such as Asia and the Middle East 015- 65 per 100000Ng et al 2017 Marked increase in UC diagnoses was noted over a 15-year period 1995-2009 In Cairo University 17 cases were recorded in 1995-1999 and 76 cases were recorded in 2005-2009 Esmat et al 2014
Both CD and UC are complex diseases genetically in which hundreds of independent genetic loci contribute to disease susceptibility Norouzinia et al 2015 Nevertheless the molecular mechanisms and functions of many IBD associated genes remain unknown In addition to genetics IBDs are powerfully influenced by microbiological and environmental aspect Norouzinia et al 2017
Genome-wide association studies GWAS have allowed a better understanding of IBD thus several genetic susceptibility loci have been identified for UC and CD Yamamoto-Furusho et al 2015 Among the genetic factors involved there are several polymorphisms in molecules of the Immune system associated with either susceptibility or protective effects to IBD progression but even with contradictory associations mainly depending on the onset adult or pediatric sample size differences and on the ethnicity-dependent genetic background Neuman et al 2012 Ng et al 2012 Peng et al 2017 Girardelli et al 2018
PTPN22 protein contains three domains including an N-terminal PTP catalytic domain an interdomain region and a C-terminal domain with four proline-rich regions that function as motifs for interaction with other protein Stanford et al 2014Tyrosine phosphatase is involved in maintaining intestinal epithelial barrier function regulating autophagosome function and immune responses to invading bacteria in intestinal cells limiting pro-inflammatory cytokine secretion in the intestine as well as controlling differentiation and function of CD4 T-cells in vivo Spalinger et al 2015 The lymphoid tyrosine phosphatase Lyp encoded by PTPN22 plays a critical role as a negative regulator of T-cell activation by dephosphorylating T-cell receptor activation dependent kinases Csk kinase Cloutier et al 1999 PTPN22 is a critical regulator of the Nod Like Receptor Family Pyrine Domain Containing 3 NLRP3 inflammasome by controlling NLRP3 tyrosine phosphorylation Further PTPN22 controls NLRP3-mediated IL-1beta secretion in an autophagy dependent manner Yilmaz et al 2018
PTPN22 gene is located on the short arm of Chromosome 1 1p132 There are 24 exons in the gene NCBI websiteAbout 21 SNPs were found in PTPN22 gene rs1310182 rs3789604 rs33996649 rs1217414 rs2476601 rs12760457 rs2488457etcSNP rs2476601 C1858T in exon 14 results in the substitution of arginine 620 with a tryptophan residue in the protein product referred to as 620W variant Spalinger et al 2016 SNP rs33996649 G788A in exon 10 mediates substitution of arginine 263 with a glutamine residue referred to as 263Q variant and affects the ability of Lyp to interact with the Csk kinase thus avoiding the formation of the complex and the resulting suppression of T-cell activationHedjoudje et al 2017 SNP rs2488457 G -1123C is located in the promoter region Chen et al 2013A transcription factor binding site for activator protein 4 AP-4 at position -1123 is predicted in the presence of the G allele rather than the C allele Jüliger et al 2003
Contradictory results have been published regarding the association of PTPN22 gene SNPs with IBD Bank et al 2014 Sfar et al 2010 Chen et al 2013 Latiano et al 2007 Diaz-Gallo et al 2011 Wagenleiter et al 2005 Zaid et al 2018 Sadr et al 2019
In Egypt studies were done regarding the association of PTPN22 gene SNPs with Type1 DM El-Kafoury et al 2014 ITP Anis et al 2011 SLE Elghzaly et al 2015 Alopecia Areata El-Zawahry et al 2013 and RA Salama et al 2014
Uptodate no studies were published regarding the association of PTPN22 gene SNPs with IBD in egyptians
Lennard-Jones et al have defined macroscopic and microscopic criteria to establish the diagnosis of Crohns disease The macroscopic diagnostic tools include physical examination endoscopy and radiology Microscopic features can be assessed on mucosal biopsy andor operative specimen The diagnosis depends on the finding of discontinuous and often granulomatous intestinal inflammation Lennard-Jones et al 1997 Diagnosis of ulcerative colitis is based on history endoscopic appearances histopathology of multiple mucosal biopsies and appropriate radiology Silverberg et al 2005 Satsangi et al 2006
The incidence pattern of UC has changed over the last two decades with incidence continuing to rise in the West and rising incidence in previously low incidence areas such as Asia and the Middle East 015- 65 per 100000Ng et al 2017 Marked increase in UC diagnoses was noted over a 15-year period 1995-2009 In Cairo University 17 cases were recorded in 1995-1999 and 76 cases were recorded in 2005-2009 Esmat et al 2014
Both CD and UC are complex diseases genetically in which hundreds of independent genetic loci contribute to disease susceptibility Norouzinia et al 2015 Nevertheless the molecular mechanisms and functions of many IBD associated genes remain unknown In addition to genetics IBDs are powerfully influenced by microbiological and environmental aspect Norouzinia et al 2017
Genome-wide association studies GWAS have allowed a better understanding of IBD thus several genetic susceptibility loci have been identified for UC and CD Yamamoto-Furusho et al 2015 Among the genetic factors involved there are several polymorphisms in molecules of the Immune system associated with either susceptibility or protective effects to IBD progression but even with contradictory associations mainly depending on the onset adult or pediatric sample size differences and on the ethnicity-dependent genetic background Neuman et al 2012 Ng et al 2012 Peng et al 2017 Girardelli et al 2018
PTPN22 protein contains three domains including an N-terminal PTP catalytic domain an interdomain region and a C-terminal domain with four proline-rich regions that function as motifs for interaction with other protein Stanford et al 2014Tyrosine phosphatase is involved in maintaining intestinal epithelial barrier function regulating autophagosome function and immune responses to invading bacteria in intestinal cells limiting pro-inflammatory cytokine secretion in the intestine as well as controlling differentiation and function of CD4 T-cells in vivo Spalinger et al 2015 The lymphoid tyrosine phosphatase Lyp encoded by PTPN22 plays a critical role as a negative regulator of T-cell activation by dephosphorylating T-cell receptor activation dependent kinases Csk kinase Cloutier et al 1999 PTPN22 is a critical regulator of the Nod Like Receptor Family Pyrine Domain Containing 3 NLRP3 inflammasome by controlling NLRP3 tyrosine phosphorylation Further PTPN22 controls NLRP3-mediated IL-1beta secretion in an autophagy dependent manner Yilmaz et al 2018
PTPN22 gene is located on the short arm of Chromosome 1 1p132 There are 24 exons in the gene NCBI websiteAbout 21 SNPs were found in PTPN22 gene rs1310182 rs3789604 rs33996649 rs1217414 rs2476601 rs12760457 rs2488457etcSNP rs2476601 C1858T in exon 14 results in the substitution of arginine 620 with a tryptophan residue in the protein product referred to as 620W variant Spalinger et al 2016 SNP rs33996649 G788A in exon 10 mediates substitution of arginine 263 with a glutamine residue referred to as 263Q variant and affects the ability of Lyp to interact with the Csk kinase thus avoiding the formation of the complex and the resulting suppression of T-cell activationHedjoudje et al 2017 SNP rs2488457 G -1123C is located in the promoter region Chen et al 2013A transcription factor binding site for activator protein 4 AP-4 at position -1123 is predicted in the presence of the G allele rather than the C allele Jüliger et al 2003
Contradictory results have been published regarding the association of PTPN22 gene SNPs with IBD Bank et al 2014 Sfar et al 2010 Chen et al 2013 Latiano et al 2007 Diaz-Gallo et al 2011 Wagenleiter et al 2005 Zaid et al 2018 Sadr et al 2019
In Egypt studies were done regarding the association of PTPN22 gene SNPs with Type1 DM El-Kafoury et al 2014 ITP Anis et al 2011 SLE Elghzaly et al 2015 Alopecia Areata El-Zawahry et al 2013 and RA Salama et al 2014
Uptodate no studies were published regarding the association of PTPN22 gene SNPs with IBD in egyptians
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None