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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
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  1. D Franchimont1,*,
  2. S Vermeire2,*,
  3. H El Housni3,
  4. M Pierik2,
  5. K Van Steen4,
  6. T Gustot1,
  7. E Quertinmont1,
  8. M Abramowicz3,
  9. A Van Gossum1,
  10. J Devière1,
  11. P Rutgeerts2
  1. 1Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium
  2. 2Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
  3. 3Department of Genetics and IRIBHM, Erasme University Hospital, ULB, Brussels, Belgium
  4. 4Centre for Statistics, Limburgs Universitair Centrum, Diepenbeek, Belgium
  1. Correspondence to:
    Dr D Franchimont
    Department of Gastroenterology, Erasme University Hospital, 808, Lennik St, 1070 Brussels, Belgium; Denis.Franchimontulb.ac.be

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.

  • PRR, pattern recognition receptor
  • TLR, toll-like receptor
  • LPS, lipopolysaccharide
  • CD, Crohn’s disease
  • UC, ulcerative colitis
  • IBD, inflammatory bowel disease
  • LRR, leucine rich repeat
  • PGN, peptidoglycan
  • IEC, intestinal epithelial cell
  • TDT, transmission disequilibrium test
  • IC, indeterminate colitis
  • ASCA, anti-Saccharomyces cerevisiae antibody
  • BI, binding index
  • SNP, single nucleotide polymorphisms
  • PCR, polymerase chain reaction
  • OR, odds ratios
  • GAR, genotype absolute risk
  • GRR, genotype relative risk
  • RR, relative risk
  • inflammatory bowel disease
  • toll-like receptor
  • tlr-4 Asp299gly
  • Crohn’s disease
  • ulcerative colitis
  • innate immunity

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Footnotes

  • * D Franchimont and S Vermeire contributed equally to this work.

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