The role of toll‐like receptor 4 Asp299Gly and Thr399Ile polymorphisms and CARD15/NOD2 mutations in the susceptibility and phenotype of Crohn's disease

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.