Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn's disease and ulcerative colitis - PubMed (original) (raw)

Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn's disease and ulcerative colitis

D Franchimont et al. Gut. 2004 Jul.

Abstract

Background and aims: Elicitation of an innate immune response to bacterial products is mediated through pattern recognition receptors (PRRs) such as the toll-like receptors (TLRs) and the NODs. The recently characterised Asp299Gly polymorphism in the lipopolysaccharide (LPS) receptor TLR4 is associated with impaired LPS signalling and increased susceptibility to Gram negative infections. We sought to determine whether this polymorphism was associated with Crohn's disease (CD) and/or ulcerative colitis (UC).

Methods: Allele frequencies of the TLR4 Asp299Gly polymorphism and the three NOD2/CARD15 polymorphisms (Arg702Trp, Gly908Arg, and Leu1007fsinsC) were assessed in two independent cohorts of CD patients (cohort 1, n = 334; cohort 2, n = 114), in 163 UC patients, and in 140 controls. A transmission disequilibrium test (TDT) was then performed on 318 inflammatory bowel disease (IBD) trios.

Results: The allele frequency of the TLR4 Asp299Gly polymorphism was significantly higher in CD (cohort 1: 11% v 5%, odds ratio (OR) 2.31 (95% confidence interval (CI) 1.28-4.17), p = 0.004; and cohort 2: 12% v 5%, OR 2.45 (95% CI 1.24-4.81), p = 0.007) and UC patients (10% v 5%, OR 2.05 (95% CI 1.07-3.93), p = 0.027) compared with the control population. A TDT on 318 IBD trios demonstrated preferential transmission of the TLR4 Asp299Gly polymorphism from heterozygous parents to affected children (T/U: 68/34, p = 0.01). Carrying polymorphisms in both TLR4 and NOD2 was associated with a genotype relative risk (RR) of 4.7 compared with a RR of 2.6 and 2.5 for TLR4 and NOD2 variants separately.

Conclusion: We have reported on a novel association of the TLR4 Asp299Gly polymorphism with both CD and UC. This finding further supports the genetic influence of PRRs in triggering IBD.

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Figures

Figure 1

(A) Allele frequencies for the NOD2 variants (Arg702Trp, Gly908Arg, and Leu1007fsinsC) and the toll-like receptor 4 (TLR4) Asp299Gly polymorphism in the Crohn’s disease (CD) cohort 1, CD cohort 2, ulcerative colitis (UC) cohort, and controls. (B) Allele frequencies for the CD14 C −260T promoter polymorphism in the four groups.

Comment in

Toll-like receptor 4 gene in IBD: further evidence for genetic heterogeneity in Europe.
Arnott ID, Ho GT, Nimmo ER, Satsangi J. Arnott ID, et al. Gut. 2005 Feb;54(2):308; author reply 309. Gut. 2005. PMID: 15647200 Free PMC article. No abstract available.
The toll-like receptor 4 (TLR4) Asp299Gly polymorphism is associated with colonic localisation of Crohn's disease without a major role for the Saccharomyces cerevisiae mannan-LBP-CD14-TLR4 pathway.
Ouburg S, Mallant-Hent R, Crusius JB, van Bodegraven AA, Mulder CJ, Linskens R, Peña AS, Morré SA. Ouburg S, et al. Gut. 2005 Mar;54(3):439-40. doi: 10.1136/gut.2004.051383. Gut. 2005. PMID: 15710998 Free PMC article. No abstract available.

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Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn's disease and ulcerative colitis - PubMed (original) (raw)