Polymorphisms of NOD2 (R702W, G908R and L1007fs) and TLR4 (Asp299Gly and Thr399Ile) genes were analyzed in 106 patients with IBD (68 with ulcerative colitis [UC], 38 with Crohn's disease [CD]) and 160 healthy controls using polymerase chain reaction-restriction fragment length polymorphism.
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.
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.
Furthermore a missense polymorphism in the TLR4 gene has been associated with a number of autoimmune conditions, including Crohn diseases, making TLR4 a viable candidate gene for investigation.
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.
Our meta-analysis suggests that TLR4T399I polymorphism is moderately associated with susceptibility to CD, and more studies are needed to confirm our conclusion.
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.
Toll-like receptor (TLR) polymorphisms, and especially TLR-4Asp299Gly and TLR-4Thr399Ile, have been linked with Crohn's disease (CD) and to a lesser extent with ulcerative colitis (UC), CD behavior, and compromised seroreactivity to microbial antigens.
D299G and T399I were related to CD only in patients carrying NOD2 variants (NOD2+/TLR4+ haplotype) (p=0.036; OR=1.924), increasing the risk to develop CD when 1007insC and TLR4 variants were both present (OR=4.886).
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 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.
This genetic study provides evidence that the three major CARD15/NOD2 variant alleles and the CD14 -159C/T polymorphism are associated with Crohn's disease (CD) susceptibility in the Saudi population; however, there is no evidence that the TLR4 (Thr399Il) or CARD15/NOD2 polymorphisms can be considered risk factors for Crohn's disease.
The polymorphisms TLR2 (rs1816702), NFKB1 (rs28362491), TNFRSF1A (rs4149570), IL6R (rs4537545), IL23R (rs11209026) and PTPN22 (rs2476601) were associated with risk of CD and the polymorphisms TLR2 (rs1816702), TLR4 (rs1554973 and rs12377632), TLR9 (rs352139), LY96 (rs11465996), NFKBIA (rs696), TNFA (rs1800629), TNFRSF1A (rs4149570), IL10 (rs3024505), IL23R (rs11209026), PTPN22 (rs2476601) and PPARG (rs1801282) were associated with risk of UC.
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.
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.
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.