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.
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.
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).
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 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.
The aim of this study was to assess the association between NOD2 polymorphisms and GDCD, and to assess the specific association between each of the 3 major allelic variants G908R, L1007P, and R702W and the clinical features of Crohn's disease.
CARD15/NOD2 polymorphisms contribute but do not alone explain concordance of Crohn's disease in monozygotic twins and, at least in a Swedish population, other polymorphisms are required.
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.
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.
A positive association between the HLA-DRB1*0103 allele and CD was detected in non-Jewish, familial cases (p = 0.0002), with risk for CD increased by 6.7 fold by the presence of an HLA-DRB1*0103 allele as compared to 1.9 fold and 19 fold by a single or two CARD15 variant alleles, respectively.
Frequency of NOD2/CARD15 variants in both sporadic and familial cases of Crohn's disease across Italy. An Italian Group for Inflammatory Bowel Disease Study.
Despite this, recent studies reported variable associations between CD and CARD15 mutations in distinct ethnic groups, thus raising the hypothesis that genetic and/or allelic heterogeneity may influence the relationship between CARD15 and CD.
Thus, NOD2 mediates the host response to bacterial muropeptides derived from peptidoglycan, an activity that is important for protection against Crohn's disease.
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.
Together, studies on Nod2 (Card15) provide a conceptual link between inflammatory disorders, such as Crohn's disease and Blau syndrome, and bacterial sensing.
In a Spanish population from Madrid, mutations of the NOD2/CARD15 gene were a marker of susceptibility to Crohn disease and were associated with ileal disease.
In this review, we summarize current information on the genetics of IBD, emphasizing the discovery of CARD15 variants as susceptibility alleles for Crohn's disease and the impact of this discovery on patient care and in delineating pathogenesis of this complex disease.