Association Between Polymorphisms in the Toll-like Receptor 4, CD14, and CARD15/NOD2 and Inflammatory Bowel Disease in the Greek Population

World J Gastroenterol. 2005 Feb 7;11(5):681-5. doi: 10.3748/wjg.v11.i5.681.


Aim: Crohn's disease (CD) and ulcerative colitis (UC) are multifactorial diseases with a significant genetic background. Apart from CARD15/NOD2 gene, evidence is accumulating that molecules related to the innate immune response such as CD14 or Toll-like receptor 4 (TLR4), are involved in their pathogenesis. In further exploring the genetic background of these diseases, we investigated the variations in the CARD15/NOD2 gene (Arg702Trp, Gly908Arg and Leu1007fsinsC), and polymorphisms in the TLR4 gene (Asp299Gly and Thr399Ile) as well as in the promoter of the CD14 gene (T/C at position -159) in Greek patients with CD and UC.

Methods: DNA was obtained from 120 patients with CD, 85 with UC and 100 healthy individuals. Genotyping was performed by allele specific PCR or by PCR-RFLP analysis.

Results: The 299Gly allele frequency of the TLR4 gene and the T allele and TT genotype frequencies of the CD14 promoter were significantly higher in CD patients only compared to healthy individuals (P = 0.026<0.05; P = 0.0048<0.01 and P = 0.047<0.05 respectively). Concerning the NOD2/CARD15 mutations the overall presence in CD patients was significantly higher than that in UC patients or in controls. Additionally, 51.67% of the CD patients were carriers of a TLR4 and/or CD14 polymorphic allele and at least one variant of the NOD2/CARD15, compared to 27% of the UC patients. It should be pointed out that both frequencies significantly increased as compared with the 10% frequency of multiple carriers found in healthy controls. A possible interaction of the NOD2/CARD15 with TLR4 and especially CD14, increased the risk of developing inflammatory bowel disease (IBD).

Conclusion: Our results indicate that co-existence of a mutation in either the TLR4 or CD14 gene, and in NOD2/CARD15 is associated with an increased susceptibility to developing CD compared to UC, and to developing either CD or UC compared to healthy individuals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Colitis, Ulcerative / epidemiology
  • Colitis, Ulcerative / genetics*
  • Crohn Disease / epidemiology
  • Crohn Disease / genetics*
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease / epidemiology
  • Genotype
  • Greece / epidemiology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Lipopolysaccharide Receptors / genetics*
  • Male
  • Membrane Glycoproteins / genetics*
  • Nod2 Signaling Adaptor Protein
  • Polymorphism, Genetic
  • Promoter Regions, Genetic
  • Receptors, Cell Surface / genetics*
  • Risk Factors
  • Toll-Like Receptor 4
  • Toll-Like Receptors


  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharide Receptors
  • Membrane Glycoproteins
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • Receptors, Cell Surface
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Toll-Like Receptors