Z Gastroenterol 2008; 46 - P213
DOI: 10.1055/s-0028-1089588

Epistasis between Toll-like receptor (TLR)-9 polymorphisms and variants in IL23R and DLG5 modulates susceptibility to Crohn's disease

HP Török 1, J Glas 2, J Konnerth 3, M Wetzke 3, P Lohse 4, T Ochsenkühn 1, M Folwaczny 2, B Göke 1, C Folwaczny 3, B Müller-Myhsok 5, S Brand 1
  • 1Universitätsklinikum Grosshadern, Medizinische Klinik und Poliklinik II, München, Germany
  • 2Universitätsklinikum München, Poliklinik für Zahnerhaltung und Parodontologie, München, Germany
  • 3Universitätsklinikum München, Chirurgische Klinik und Poliklinik Innenstadt, München, Germany
  • 4Universitätsklinikum Grosshadern, Institut für Klinische Chemie, München, Germany
  • 5Max-Planck-Institut für Psychiatrie, München, Germany

Aims: The identification of NOD2 provides important genetic evidence for the role of innate pattern recognition receptors in the pathogenesis of Crohn's disease (CD). Recognition of bacterial DNA via TLR9 seems to be crucial for the maintenance of gut homeostasis and gut inflammation. We previously showed that a promoter polymorphism in TLR9 (-1237 T/C) further increases disease risk in CD patients bearing NOD2 mutations. Here, we tested for genetic interaction of this polymorphism with variants in IL23R, and in other susceptibility genes for CD and analyzed the role of further common TLR9 polymorphisms in the susceptibility to CD.

Methods: The SNPs -1237T/C, 2848A/G, 1174 A/G, 1923 A/C and 1486 C/T in TLR9, the main CD-associated variants in 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. Association with disease susceptibility and phenotype, and epistatic gene-gene interactions were analyzed.

Results: None of the TLR9 polymorphisms showed independent association with CD or ulcerative colitis. Significant gene-gene interactions of the promoter polymorphism -1237 T/C with IL23R variants (most significantly with rs1004819, p=0.0007), were observed, with a particular high frequency of -1237C carriers among CD patients carrying CD-protective IL23R variants. Thus, after stratification with regard to the TLR9–1237 genotype, a significant association of IL23R polymorphisms was observed only in patients carrying the frequent (-1237TT) genotype, and not in patients with the rare -1237C variant. In contrast, the frequency of TLR9–1237C carriers was higher among CD patients homozygous or heterozygous for the DLG5 variant 113A (p=0.00004, OR 2.53, 95% CI 1.60–3.99).

Conclusion: Our results provide evidence for strong genetic interactions between a polymorphism in TLR9 and CD associated variants in IL23R as well as variants in DLG5, differentially modulating susceptibility to CD. These genetic observations complement functional data sustaining an important role of bacterial recognition via TLR9 in maintenance of gut homeostasis and development of gut inflammation.