Inflammatory Bowel Disease
Subject Category: Inflammatory Bowel Disease
Am J Gastroenterol 2009; 104:1723–1733; doi:10.1038/ajg.2009.184; published online 19 May 2009
Epistasis Between Toll-Like Receptor-9 Polymorphisms and Variants in NOD2 and IL23R Modulates Susceptibility to Crohn's Disease
Helga P Török MD1, Jürgen Glas MD1,2, Ilona Endres3, Laurian Tonenchi MD1,2, Molla Y Teshome MD3,4, Martin Wetzke3, Wolfram Klein MD5, Peter Lohse MD6, Thomas Ochsenkühn MD1, Matthias Folwaczny DMD2, Burkhard Göke MD1, Christian Folwaczny MD3, Bertram Müller-Myhsok MD7 and Stephan Brand MD1
- 1Department of Internal Medicine II, Campus Grosshadern, University of Munich, Munich, Germany
- 2Clinic for Preventive Dentistry and Parodontology, University of Munich, Munich, Germany
- 3Department of Surgery, Campus Innenstadt, University of Munich, Munich, Germany
- 4Jimma University Hospital, Jimma, Ethiopia
- 5Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany
- 6Institute of Clinical Chemistry, Campus Grosshadern, University of Munich, Munich, Germany
- 7Max Planck Institute of Psychiatry, Munich, Germany
Correspondence: Helga-Paula Török, MD, Department of Internal Medicine II, Campus Grosshadern, University of Munich, Marchioninistr. 15, Munich D-81377, Germany. E-mail: helga.toeroek@med.uni-muenchen.de
Received 24 April 2008; Accepted 12 November 2008; Published online 19 May 2009.
Abstract
OBJECTIVES:
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).
METHODS:
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.
RESULTS:
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).
CONCLUSIONS:
Our results provide evidence for genetic interactions between polymorphisms in TLR9 and CD-associated variants in NOD2, IL23R, and DLG5, differentially modulating CD susceptibility.
