The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases

Genes Immun. 2007 Jul;8(5):387-97. doi: 10.1038/sj.gene.6364398. Epub 2007 May 31.

Abstract

The intestinal flora has long been thought to play a role either in initiating or in exacerbating the inflammatory bowel diseases (IBD). Host defenses, such as those mediated by the Toll-like receptors (TLR), are critical to the host/pathogen interaction and have been implicated in IBD pathophysiology. To explore the association of genetic variation in TLR pathways with susceptibility to IBD, we performed a replication study and pooled analyses of the putative IBD risk alleles in NFKB1 and TLR4, and we performed a haplotype-based screen for association to IBD in the TLR genes and a selection of their adaptor and signaling molecules. Our genotyping of 1539 cases of IBD and pooled analysis of 4805 cases of IBD validates the published association of a TLR4 allele with risk of IBD (odds ratio (OR): 1.30, 95% confidence interval (CI): 1.15-1.48; P=0.00017) and Crohn's disease (OR: 1.33, 95% CI: 1.16-1.54; P=0.000035) but not ulcerative colitis. We also describe novel suggestive evidence that TIRAP (OR: 1.16, 95% CI: 1.04-1.30; P=0.007) has a modest effect on risk of IBD. Our analysis, therefore, offers additional evidence that the TLR4 pathway - in this case, TLR4 and its signaling molecule TIRAP - plays a role in susceptibility to IBD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease*
  • Genotype
  • Haplotypes
  • Humans
  • Inflammatory Bowel Diseases / genetics*
  • Inflammatory Bowel Diseases / immunology
  • Longitudinal Studies
  • Male
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism
  • Polymorphism, Single Nucleotide*
  • Receptors, Interleukin-1 / genetics*
  • Receptors, Interleukin-1 / metabolism
  • Signal Transduction
  • Toll-Like Receptor 4 / genetics*
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 4 / metabolism
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / metabolism

Substances

  • Membrane Glycoproteins
  • Receptors, Interleukin-1
  • TIRAP protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Toll-Like Receptors