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

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

Maureen J Koslowski et al. PLoS One. 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.

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Conflict of interest statement

Competing Interests: MJK, JB, EFS and JW have a pending patent application regarding TCF-4 SNP detection.

Figures

Figure 1
Figure 1. Sequencing of TCF-4 (TCF7L2) 5′upstream putative promoter region.

Sequencing of a 2.1 kb upstream region was performed in 10 healthy controls and 10 patients with ileal Crohn's disease. Putative regulatory regions were determined using promoter prediction software. Likely and marginal prediction sites are depicted as red boxes (upper panel). Relative location of identified variants is marked via grey dashes (upper part) and their allele frequency is demonstrated via bars for controls as well as patients (lower part).

Figure 2
Figure 2. Distribution of haploblocks of TCF-4 (TCF7L2).

Both colour schemes (a and b) illustrate the linkage disequilibria. The variants are listed in the upper part of a and b, respectively. Haplotypes for TCF-4 (TCF7L2) rs3814570 (SNP1), rs10885394 (SNP2), rs10885395 (SNP3) and SNPs associated with diabetes in the Vienna cohort are shown in a. A missing number for D′ or r2 equals 1. Figure 2b: HapMap data based haplotype blocks and linkage disequilibria (LD) for TCF-4 (TCF7L2) polymorphisms. The intensity of red colouring in b is proportional to the extent of D′ or r 2 respectively and a missing number for each of them equals. The observed SNP in the putative promoter region is not part of any significant haplotype block.

Figure 3
Figure 3. Differences in frequency distribution of rs3814570 in the different disease subgroups compared to healthy controls.

Odds ratios and confidence intervals for the different comparisons are shown. The frequency distribution of rs3814570 was analyzed in different cohorts and combined samples: odds ratios and 95% confidence interval for allele frequency (upper panel) and allele positivity (amount of all T- allele carriers, lower panel) are shown for patients with ulcerative colitis (UC) (left panel), Crohn's disease (CD) patients with solely colonic involvement (L2, middle panel) and finally patients classified as either L1 (solely ileal) or L3 (ileal and colonic involvement) (right panel) compared to healthy control individuals.

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