Association between polymorphisms in the Toll-like receptor 4, CD14, and CARD15/NOD2 and inflammatory bowel disease in the Greek population.
OBJECTIVE
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).


CONCLUSIONS
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.
Gazouli
Maria
M
Department of Histology-Embryology, 53 Antaiou St. Ano Patisia, 11146 Athens, Greece.
Mantzaris
Gerassimos
G
Kotsinas
Athanassios
A
Zacharatos
Panayotis
P
Papalambros
Efstathios
E
Archimandritis
Athanassios
A
Ikonomopoulos
John
J
Gorgoulis
Vassilis-G
VG
D003093:Colitis, Ulcerative / Q000453:epidemiology / Q000235:genetics*; D003424:Crohn Disease / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D006115:Greece / Q000453:epidemiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D018950:Lipopolysaccharide Receptors / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D053473:Nod2 Signaling Adaptor Protein; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics*; D012307:Risk Factors; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D047908:Intracellular Signaling Peptides and Proteins; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors