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
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany.
PLoS One. 2009;4(2):e4496. doi: 10.1371/journal.pone.0004496. Epub 2009 Feb 16.
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.
潘氏细胞抗菌α-防御素、人防御素（HD）-5和-6的表达降低是回肠克罗恩病（CD）的特征。TCF-4（也称为TCF7L2）是一种Wnt信号通路转录因子，可协调潘氏细胞分化，直接调节HD-5和-6的表达，并且先前在一部分回肠CD患者中与这些抗菌肽的减少有关。为了研究TCF-4与回肠CD的潜在遗传关联，我们对一小群回肠CD患者和对照（每组n = 10）的TCF-4 5'侧翼区域的2.1 kb进行了测序。我们鉴定出8个单核苷酸多态性（SNP），其中3个（rs3814570、rs10885394、rs10885395）处于连锁不平衡状态，并且在患者中更频繁地出现；其中一个（rs3814570）位于一个预测的调控区域。我们在三组炎症性肠病（IBD）患者和对照中对该SNP进行了高通量分析。总共使用1399名健康个体、785名溃疡性结肠炎（UC）患者、225名仅患有结肠疾病的CD患者和784名累及回肠的CD患者来确定频率分布。在一项综合分析中，我们发现rs3814570与回肠CD相关，但与结肠CD或UC均无关（等位基因阳性：比值比1.27，95%置信区间1.07至1.52，p = 0.00737），这在具有狭窄行为的回肠CD患者中最为明显（等位基因频率：比值比1.32，95%置信区间1.08至1.62，p = 0.00686）或上消化道有额外累及的患者中（等位基因频率：比值比1.38，95%置信区间1.03至1.84，p = 0.02882）。新发现的TCF-4与回肠CD的遗传关联提供了证据，表明潘氏细胞α-防御素的减少是疾病发病机制中的一个主要因素。
