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Genetic Variants of Wnt Transcription Factor TCF-4 (TCF7L2) Putative Promoter Region Are Associated with Small Intestinal Crohn's Disease
- Source :
- PLoS ONE, PloS one, vol 4, iss 2, PLoS ONE, Vol 4, Iss 2, p e4496 (2009)
- Publication Year :
- 2009
- Publisher :
- Public Library of Science (PLoS), 2009.
-
Abstract
- Reduced expression of Paneth cell antimicrobial alpha-defensins, human defensin (HD)-5 and -6, characterizes Crohn's disease (CD) of the ileum. TCF-4 (also named TCF7L2), a Wnt signalling pathway transcription factor, orchestrates Paneth cell differentiation, directly regulates the expression of HD-5 and -6, and was previously associated with the decrease of these antimicrobial peptides in a subset of ileal CD. To investigate a potential genetic association of TCF-4 with ileal CD, we sequenced 2.1 kb of the 5' flanking region of TCF-4 in a small group of ileal CD patients and controls (n = 10 each). We identified eight single nucleotide polymorphisms (SNPs), of which three (rs3814570, rs10885394, rs10885395) were in linkage disequilibrium and found more frequently in patients; one (rs3814570) was thereby located in a predicted regulatory region. We carried out high-throughput analysis of this SNP in three cohorts of inflammatory bowel disease (IBD) patients and controls. Overall 1399 healthy individuals, 785 ulcerative colitis (UC) patients, 225 CD patients with colonic disease only and 784 CD patients with ileal involvement were used to determine frequency distributions. We found an association of rs3814570 with ileal CD but neither with colonic CD or UC, in a combined analysis (allele positivity: OR 1.27, 95% CI 1.07 to 1.52, p = 0.00737), which was the strongest in ileal CD patients with stricturing behaviour (allele frequency: OR 1.32, 95% CI 1.08 to1.62, p = 0.00686) or an additional involvement of the upper GIT (allele frequency: OR 1.38, 95% CI 1.03 to1.84, p = 0.02882). The newly identified genetic association of TCF-4 with ileal CD provides evidence that the decrease in Paneth cell alpha-defensins is a primary factor in disease pathogenesis.
- Subjects :
- Male
Immunology/Innate Immunity
Nod2 Signaling Adaptor Protein
lcsh:Medicine
Crohn's Disease
Inflammatory bowel disease
Oral and gastrointestinal
Linkage Disequilibrium
0302 clinical medicine
Crohn Disease
2.1 Biological and endogenous factors
Aetiology
lcsh:Science
Promoter Regions, Genetic
Defensin
Genetics and Genomics/Genetics of Disease
Genetics and Genomics/Medical Genetics
0303 health sciences
Crohn's disease
Multidisciplinary
Single Nucleotide
3. Good health
Gastroenterology and Hepatology/Gastrointestinal Infections
medicine.anatomical_structure
Female
030211 gastroenterology & hepatology
TCF Transcription Factors
Sequence Analysis
Transcription Factor 7-Like 2 Protein
Biotechnology
Research Article
Adult
Paneth Cells
Adolescent
Genotype
General Science & Technology
Single-nucleotide polymorphism
Biology
Autoimmune Disease
Polymorphism, Single Nucleotide
digestive system
Gastroenterology and Hepatology/Small Intestine
Promoter Regions
Young Adult
03 medical and health sciences
Genetic
Clinical Research
Ileum
Genetics
medicine
Humans
Genetic Predisposition to Disease
Polymorphism
Allele
Allele frequency
Alleles
030304 developmental biology
Gastroenterology and Hepatology/Inflammatory Bowel Disease
lcsh:R
Inflammatory Bowel Disease
Genetic Variation
DNA
Sequence Analysis, DNA
medicine.disease
Paneth cell
Immunology
lcsh:Q
Digestive Diseases
TCF7L2
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 4
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....e1f174c089408300a95bb36dd79c610b