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.
Mutations in the NOD2/caspase recruitment domains 15 (CARD15) and in the Toll-like receptor 4 (TLR4) gene have been associated with increased susceptibility for CD.
We observed that the R702W and 1007fs Nod2 alleles and the A299GTlr4 alleles were significantly more prevalent in patients with CD as compared to healthy controls or patients with ulcerative colitis.
In addition, interaction of TLR4 with the caspase recruitment domain containing protein 15 gene (CARD15) was studied in patients with Crohn's disease (CD).
In addition, interaction of TLR4 with the caspase recruitment domain containing protein 15 gene (CARD15) was studied in patients with Crohn's disease (CD).
We investigated polymorphisms of CARD15, TLR4, and OCTN, and environmental factors in a monozygotic twin pair with Crohn's disease and their first-degree relatives.
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.
One non-synonymous SNP in TLR4 and two non-synonymous SNPs in CARD15, previously associated with atherosclerosis and Crohn's disease, respectively, were also studied.
The TLR4Asp299Gly and Thr399Ile polymorphisms were genotyped and tested for case-control frequency differences in a New Zealand white cohort of 389 Crohn's disease (CD) patients, 405 ulcerative colitis (UC) patients, and 416 population controls.
The nucleotide oligomerization domain 2/caspase activating recruitment domain 15 (NOD2/CARD15) gene located at 16q12 is strongly associated with susceptibility to CD in white people but is absent in adult Asian patients, whereas the role of Toll-like receptor 4 (TLR4) polymorphisms has also been reported.
Nevertheless, the significance of the TLR4 299G and TLR9-1237C associations with CD worldwide was confirmed by a meta-analysis test using our datasets and datasets from previously published studies.
Hyperexpression of FcgammaRI and TLR4 on MCs was related to the high frequency of TNF-alpha expression in CD, suggesting the activation of MCs via these receptors in vivo.
Nevertheless, the significance of the TLR4 299G and TLR9-1237C associations with CD worldwide was confirmed by a meta-analysis test using our datasets and datasets from previously published studies.
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.
A cohort of 231 Israeli CD patients previously genotyped for the single nucleotide polymorphisms (SNPs) in the CARD15, TLR4 susceptibility genes for CD, was analyzed for the 3'-untranslated region (UTR) SNP of the NFKBIA gene in comparison to 100 healthy ethnically matched controls.
In this two-center, retrospective German and Hungarian cohort study, patients with Crohn's disease (CD) (n = 379; German n = 235, Hungarian n = 144) and ulcerative colitis (UC) (n = 263; German n = 145, Hungarian n = 118) and healthy controls (n = 605; German n = 403, Hungarian n = 202) were genotyped for the presence of the CD14 c.1-260C>T promoter variant and the TLR4 c.896A>G (p.D299G) variant by melting curve analysis using fluorescence resonance energy transfer probes.
In conclusion, we propose the absence of NOD2/TLR4 cross-tolerance as a central mechanism for the increased susceptibility to Crohn's disease in individuals with NOD2 mutations.
To examine whether TLR4Asp299Gly, CD14-260C/T, TNF-1031T/C, TNF-863C/A, TNF-857C/T, TACE-172C/T, and TACE-154C/A polymorphisms are associated with Crohn disease in the Ashkenazi Jewish population, we analyzed families with at least 1 child with Crohn disease for association with these mutations using a family-based association test (transmission disequilibrium test) for analysis.
Our aim was to investigate whether mutations in various genes other than NOD2/CARD15 or TLR4 associated with CD (NOD1/CARD4, DLG5 and DEFB1) may influence the presence of antibodies against bacterial proteins and carbohydrates in a Hungarian cohort of CD patients.
These findings confirm that, in our IBD patients selected from Southern Italy, the NOD2/CARD15, but not TLR4 SNPs, are associated with increased risk of CD.