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 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.
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany.
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Koslowski
authors.forename: Irmgard
authors.initials: I
authors.lastname: Kübler
authors.forename: Mathias
authors.initials: M
authors.lastname: Chamaillard
authors.forename: Elke
authors.initials: E
authors.lastname: Schaeffeler
authors.forename: Walter
authors.initials: W
authors.lastname: Reinisch
authors.forename: Guoxing
authors.initials: G
authors.lastname: Wang
authors.forename: Julia
authors.initials: J
authors.lastname: Beisner
authors.forename: Alexander
authors.initials: A
authors.lastname: Teml
authors.forename: Laurent
authors.initials: L
authors.lastname: Peyrin-Biroulet
authors.forename: Stefan
authors.initials: S
authors.lastname: Winter
authors.forename: Klaus R
authors.initials: KR
authors.lastname: Herrlinger
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.forename: Séverine
authors.initials: S
authors.lastname: Vermeire
authors.forename: Rachel
authors.initials: R
authors.lastname: Cooney
authors.forename: Klaus
authors.initials: K
authors.lastname: Fellermann
authors.forename: Derek
authors.initials: D
authors.lastname: Jewell
authors.forename: Charles L
authors.initials: CL
authors.lastname: Bevins
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Eduard F
authors.initials: EF
authors.lastname: Stange
authors.forename: Jan
authors.initials: J
authors.lastname: Wehkamp
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D003424:Crohn Disease / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007082:Ileum / Q000378:metabolism / Q000473:pathology*; D015810:Linkage Disequilibrium; D008297:Male; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D019879:Paneth Cells / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017422:Sequence Analysis, DNA; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein; D055815:Young Adult
chemical_list: D053473:Nod2 Signaling Adaptor Protein; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein