Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn's disease

Maureen J. Koslowski, Irmgard Kübler, Mathias Chamaillard, Elke Schaeffeler, Walter Reinisch, Guoxing Wang, Julia Beisner, Alexander Teml, Laurent Peyrin-Biroulet, Stefan Winter, Klaus R. Herrlinger, Paul Rutgeerts, Séverine Vermeire, Rachel Cooney, Klaus Fellermann, Derek Jewell, Charles L Bevins, Matthias Schwab, Eduard F. Stange, Jan Wehkamp

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

Reduced expression of Paneth cell antimicrobial α-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 α-defensins is a primary factor in disease pathogenesis.

Original languageEnglish (US)
Article numbere4496
JournalPLoS One
Volume4
Issue number2
DOIs
StatePublished - Feb 16 2009

Fingerprint

Wnt Proteins
TCF Transcription Factors
Intestinal Diseases
Crohn disease
Genetic Promoter Regions
Crohn Disease
Ileal Diseases
Transcription Factors
transcription factors
promoter regions
Defensins
Paneth Cells
Colonic Diseases
colitis
Ulcerative Colitis
Gene Frequency
single nucleotide polymorphism
gene frequency
Single Nucleotide Polymorphism
Polymorphism

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Koslowski, M. J., Kübler, I., Chamaillard, M., Schaeffeler, E., Reinisch, W., Wang, G., ... Wehkamp, J. (2009). Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn's disease. PLoS One, 4(2), [e4496]. https://doi.org/10.1371/journal.pone.0004496

Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn's disease. / Koslowski, Maureen J.; Kübler, Irmgard; Chamaillard, Mathias; Schaeffeler, Elke; Reinisch, Walter; Wang, Guoxing; Beisner, Julia; Teml, Alexander; Peyrin-Biroulet, Laurent; Winter, Stefan; Herrlinger, Klaus R.; Rutgeerts, Paul; Vermeire, Séverine; Cooney, Rachel; Fellermann, Klaus; Jewell, Derek; Bevins, Charles L; Schwab, Matthias; Stange, Eduard F.; Wehkamp, Jan.

In: PLoS One, Vol. 4, No. 2, e4496, 16.02.2009.

Research output: Contribution to journalArticle

Koslowski, MJ, Kübler, I, Chamaillard, M, Schaeffeler, E, Reinisch, W, Wang, G, Beisner, J, Teml, A, Peyrin-Biroulet, L, Winter, S, Herrlinger, KR, Rutgeerts, P, Vermeire, S, Cooney, R, Fellermann, K, Jewell, D, Bevins, CL, Schwab, M, Stange, EF & Wehkamp, J 2009, 'Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn's disease', PLoS One, vol. 4, no. 2, e4496. https://doi.org/10.1371/journal.pone.0004496
Koslowski, Maureen J. ; Kübler, Irmgard ; Chamaillard, Mathias ; Schaeffeler, Elke ; Reinisch, Walter ; Wang, Guoxing ; Beisner, Julia ; Teml, Alexander ; Peyrin-Biroulet, Laurent ; Winter, Stefan ; Herrlinger, Klaus R. ; Rutgeerts, Paul ; Vermeire, Séverine ; Cooney, Rachel ; Fellermann, Klaus ; Jewell, Derek ; Bevins, Charles L ; Schwab, Matthias ; Stange, Eduard F. ; Wehkamp, Jan. / Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn's disease. In: PLoS One. 2009 ; Vol. 4, No. 2.
@article{3a674b438dcd4eff94beb8faafd5ee5a,
title = "Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn's disease",
abstract = "Reduced expression of Paneth cell antimicrobial α-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 α-defensins is a primary factor in disease pathogenesis.",
author = "Koslowski, {Maureen J.} and Irmgard K{\"u}bler and Mathias Chamaillard and Elke Schaeffeler and Walter Reinisch and Guoxing Wang and Julia Beisner and Alexander Teml and Laurent Peyrin-Biroulet and Stefan Winter and Herrlinger, {Klaus R.} and Paul Rutgeerts and S{\'e}verine Vermeire and Rachel Cooney and Klaus Fellermann and Derek Jewell and Bevins, {Charles L} and Matthias Schwab and Stange, {Eduard F.} and Jan Wehkamp",
year = "2009",
month = "2",
day = "16",
doi = "10.1371/journal.pone.0004496",
language = "English (US)",
volume = "4",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "2",

}

TY - JOUR

T1 - Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn's disease

AU - Koslowski, Maureen J.

AU - Kübler, Irmgard

AU - Chamaillard, Mathias

AU - Schaeffeler, Elke

AU - Reinisch, Walter

AU - Wang, Guoxing

AU - Beisner, Julia

AU - Teml, Alexander

AU - Peyrin-Biroulet, Laurent

AU - Winter, Stefan

AU - Herrlinger, Klaus R.

AU - Rutgeerts, Paul

AU - Vermeire, Séverine

AU - Cooney, Rachel

AU - Fellermann, Klaus

AU - Jewell, Derek

AU - Bevins, Charles L

AU - Schwab, Matthias

AU - Stange, Eduard F.

AU - Wehkamp, Jan

PY - 2009/2/16

Y1 - 2009/2/16

N2 - Reduced expression of Paneth cell antimicrobial α-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 α-defensins is a primary factor in disease pathogenesis.

AB - Reduced expression of Paneth cell antimicrobial α-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 α-defensins is a primary factor in disease pathogenesis.

UR - http://www.scopus.com/inward/record.url?scp=84887212530&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887212530&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0004496

DO - 10.1371/journal.pone.0004496

M3 - Article

AN - SCOPUS:84887212530

VL - 4

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 2

M1 - e4496

ER -