Török Helga P, Glas Jürgen, Endres Ilona, Tonenchi Laurian, Teshome Molla Y, Wetzke Martin, Klein Wolfram, Lohse Peter, Ochsenkühn Thomas, Folwaczny Matthias, Göke Burkhard, Folwaczny Christian, Müller-Myhsok Bertram, Brand Stephan
Department of Internal Medicine II, Campus Grosshadern, University of Munich, Munich, Germany.
Am J Gastroenterol. 2009 Jul;104(7):1723-33. doi: 10.1038/ajg.2009.184. Epub 2009 May 19.
Recent data suggest functional interactions between NOD2 and other receptors of the innate immune system modulating inflammatory responses. Here we analyzed the role of Toll-like receptor 9 (TLR-9) gene variants with respect to susceptibility to inflammatory bowel disease (IBD) and tested for genetic interactions with NOD2 and other susceptibility genes for Crohn's disease (CD).
The single-nucleotide polymorphisms (SNPs) -1237T/C (rs5743836) and 2848A/G (rs352140=p.Pro545Pro) in TLR9, the main CD-associated variants within the genes for NOD2, IL23R, ATG16L1, and variants in the IBD5 locus and in the DLG5 gene were assessed in 956 patients with IBD (606 CD and 350 ulcerative colitis) and in 792 healthy controls. The associations with disease susceptibility and phenotype, and epistatic gene-gene interactions, were analyzed.
The TLR9 -1237T/C polymorphism showed significant interactions with NOD2 mutations. The frequency of -1237C was significantly higher in CD patients with at least one NOD2 mutation (P=0.004 vs. controls, odds ratio (OR) 1.60, 95% confidence interval (CI) (1.15-2.21)) and further increased in CD patients with two mutated NOD2 alleles (P=0.002 vs. controls, OR 2.37, 95% CI (1.35-4.15)). Significant gene-gene interactions were also observed for the TLR9 polymorphism -1237T/C with IL23R variants (most significantly with rs1004819, P=0.0007), with a particular high frequency of -1237C in CD patients carrying CD-protective IL23R variants. Epistatic interactions of the TLR9 -1237T/C SNP were also noted with the DLG5 113G/A variant (P=0.0007).
Our results provide evidence for genetic interactions between polymorphisms in TLR9 and CD-associated variants in NOD2, IL23R, and DLG5, differentially modulating CD susceptibility.
近期数据表明NOD2与先天性免疫系统的其他受体之间存在功能相互作用，可调节炎症反应。在此，我们分析了Toll样受体9（TLR-9）基因变异在炎症性肠病（IBD）易感性方面的作用，并测试了其与NOD2及克罗恩病（CD）其他易感基因的遗传相互作用。
对956例IBD患者（606例CD和350例溃疡性结肠炎）及792例健康对照者，评估了TLR9基因中的单核苷酸多态性（SNP）-1237T/C（rs5743836）和2848A/G（rs352140 = p.Pro545Pro）、NOD2基因内主要的CD相关变异、IL23R、ATG16L1，以及IBD5基因座和DLG5基因中的变异。分析了这些变异与疾病易感性和表型的关联，以及上位性基因-基因相互作用。
TLR9 -1237T/C多态性与NOD2突变存在显著的相互作用。在至少有一个NOD2突变的CD患者中，-1237C的频率显著更高（与对照组相比，P = 0.004，优势比（OR）1.60，95%置信区间（CI）（1.15 - 2.21）），在有两个NOD2突变等位基因的CD患者中进一步升高（与对照组相比，P = 0.002，OR 2.37，95% CI（1.35 - 4.15））。还观察到TLR9多态性-1237T/C与IL23R变异存在显著的基因-基因相互作用（与rs1004819最为显著，P = 0.0007），在携带CD保护性IL23R变异的CD患者中，-1237C的频率特别高。TLR9 -1237T/C SNP与DLG5 113G/A变异也存在上位性相互作用（P = 0.0007）。
我们的结果为TLR9多态性与NOD2、IL23R和DLG5中CD相关变异之间的遗传相互作用提供了证据，这些相互作用以不同方式调节CD易感性。
