The role of toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and CARD15/NOD2 mutations in the susceptibility and phenotype of Crohn's disease
Article first published online: 14 DEC 2006
Copyright © 2005 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 11, Issue 7, pages 645–652, July 2005
How to Cite
Brand, S., Konrad, A., Crispin, A., Göke, B., Lohse, P. and Ochsenkühn, T. (2005), The role of toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and CARD15/NOD2 mutations in the susceptibility and phenotype of Crohn's disease. Inflamm Bowel Dis, 11: 645–652. doi: 10.1097/01.MIB.0000168372.94907.d2
- Issue published online: 14 DEC 2006
- Article first published online: 14 DEC 2006
- Manuscript Accepted: 19 APR 2005
- Manuscript Received: 7 DEC 2004
- DFG. Grant Number: (BR 1912/3-1)
- University of Munich (FöFoLe. Grant Number: Nr. 264)
- genetics of Crohn's disease;
- inflammatory bowel disease;
- Toll-like receptor
Background: We investigated the influence of 2 common Toll-like receptor 4 (TLR4) polymorphisms on susceptibility and disease characteristics of Crohn's disease (CD).
Methods: Genomic DNA from 204 patients with CD and 199 unrelated controls was analyzed for the presence of 2 single nucleotide polymorphisms in the TLR4 gene, resulting in the amino acid substitutions Asp299Gly and Thr399Ile. In addition, the carrier status for the 3 common CD-associated CARD15/NOD2 gene mutations, Arg702Trp, Gly908Arg, and 1007fs, was determined. The frequency of the different genotypes was compared, and a detailed genotype-phenotype correlation was performed.
Results: An almost 2-fold increase in the frequency of the TLR4 Asp299Gly phenotype was observed in patients with CD (14.2%) compared with healthy controls (7.5%, P = 0.038, odds ratio = 2.03). The prevalence of a stricturing phenotype was increased in patients heterozygous for 1 of the TLR4 polymorphisms studied (Asp299Gly, 34.5%; Thr399Ile, 36.7%) compared with patients with wild-type TLR4 (17.1% and 16.7%; P = 0.04 and 0.02, respectively). The presence of the Asp299Gly polymorphism in the absence of CARD15/NOD2 mutations was a particularly strong predictor of the stricturing disease phenotype that was present in 47.4% of the patients with Asp299Gly+/NOD2− compared with 10.1% of the patients with the Asp299Gly−/NOD2+ status (P = 0.0009; P = 0.0004 for Thr399Ile+/NOD2− versus Thr399Ile−/NOD2+). In contrast, there was a trend toward a higher prevalence of the penetrating phenotype in the TLR4−/NOD2+ group (71.6%) compared with the TLR4+/NOD2− group (47.4%, P = 0.059).
Conclusions: The TLR4 Asp299Gly polymorphism is a risk factor for CD. TLR4 and CARD15/NOD2 mutations may contribute to distinct disease phenotypes.