Thus, NOD2 mediates the host response to bacterial muropeptides derived from peptidoglycan, an activity that is important for protection against Crohn's disease.
Furthermore, mutant mice bearing the orthologue of the major CD-associated NOD2(3020ins) allele showed increased susceptibility to DSS-induced colitis.However, many questions remain open.
In contrast, PBMCs from a patient homozygous for the Nod2 R702W mutation, also associated with Crohn disease, displayed normal response to Gram-negative bacterial peptidoglycan.
From the CARD15 gene mutations in the adult Crohn's disease population the 1007finsC, while in the pediatric population the 1007finsC and the G908R were significantly associated with an increased risk for Crohn's disease.
Ileal involvement was more common in Crohn's disease patients with CARD15 mutations as opposed to patients without CARD15 mutations (ORadj.smoking 3.6; p <0.001).
These findings suggest that genetic variants at the 5q31 (IBD5) locus may hasten the onset of Crohn disease and cooperate with CARD15 in disease causation.
The association of the SLC22A -TC haplotype and CARD15 alleles with ileal disease suggests that these variants have biologically intertwined effects in the pathogenesis of CD.
Genotype-phenotype analysis demonstrated that CARD15 variants were associated with ileal disease (p=0.0006, OR = 9.3, CI = 2.2-34) and protective for colonic CD (p = 0.01, OR = 0.18).
In total, 32.4% of Crohn's disease patients carried at least one mutant allele within NOD2/CARD15 compared to 13.2% of patients with ulcerative colitis (P = 0.0002) and to 11.5% of controls (P<0.0001).
There is no increased risk of CD for individuals carrying only a single copy of these NOD2/ CARD15 variants, whereas individuals carrying two copies have a 5-15-fold increased risk.
The aim of this study was to determine the significance of the NOD2/CARD15 mutations in Jewish CD patients in Israel, and more specifically, to compare the significance of the mutations to the expression of CD in the Ashkenazi and Sephardic Jewish populations.
Together, studies on Nod2 (Card15) provide a conceptual link between inflammatory disorders, such as Crohn's disease and Blau syndrome, and bacterial sensing.
Dissection of the molecular events coupling CARD15 mutation to Crohn's disease has also been intensively investigated and, while not resolved as of yet, has significantly advanced understanding of the intestinal immune response to microbial challenge.
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.
In comparison to controls the A allele and the AA genotype frequencies of the single nucleotide polymorphisms in the 3'-UTR were significantly increased only in Crohn's disease patients without a variation in the CARD15 gene.