The frequency of NOD2 mutations was higher in cases from families affected only with CD and was significantly increased in ileal-specific disease cases compared with colon-specific disease (26.9% vs. 12.7%, P = 0.0004).
Analysis of the CD population without NOD2 homozygotes and compound heterozygotes revealed a more significant decrease in IL-1ra genotype 1/1 compared to controls (P=0.038).
Although patients with CD had a younger age at spondylarthritis onset than did those with UC (22.4 years versus 26.4 years; P = 0.01), no association was noted between the NOD2 variants linked with CD and age at spondylarthritis onset.
Univariate analysis showed that CD-associated NOD2 variants were significantly associated with fibrostenosing disease in each cohort (P = 0.049 and P = 0.002, respectively).
The identification of Crohn's disease-associated NOD2 genetic variants that appear to alter the innate immune response to bacteria is a seminal finding that perhaps is the greatest advance toward understanding the pathogenesis of IBD in decades.
The recent identification of the IBD1 gene (NOD2) with mutations that are associated with susceptibility to Crohn's disease will have a major impact on the understanding of the genetics of this disease.
Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects.
We confirm reports that the CARD153020insC mutation increases the susceptibility to Crohn's disease, but we do not confirm this relationship for CARD15 G2722C.
The association of polymorphisms in the CARD15 gene with Crohn's disease (CD) demonstrates the relevance of activated transcription factor NF(kappa)B in mononuclear cells.
The underlying genetic model is thought to involve multiple genes with complex interactions between disease loci, and the NOD2 gene on chromosome 16 has recently been identified as a CD susceptibility locus.
Both of these proteins interact with the apoptotic speck-like protein involved in caspase-1 activation and regulation of nuclear factor kappa B transcription; furthermore cryopyrin contains regions of homology with the nucleotide-binding oligomerization domain 2 protein, which is associated with susceptibility to Crohn's disease.
The new information summarized here includes: the discovery of the association of the NOD2 gene with Crohn's disease; the role of bacteria and the modulating effects of probiotics; the inverse association of appendectomy and ulcerative colitis; progress in imaging based on magnetic resonance imaging and leukocyte scintigraphy; assessment of the value of anti-Saccharomyces cerevisiae antibodies in the screening of inflammatory bowel disease and differentiation between ulcerative colitis and Crohn's disease; and risk factors and management of dysplasia and cancer.
Thus, NOD2 mediates the host response to bacterial muropeptides derived from peptidoglycan, an activity that is important for protection against Crohn's disease.
CARD15/NOD2, a member of the Ced4 superfamily which includes Apaf-1 and CARD4/NOD1, has recently been associated with genetic predisposition to CD but additional genetic factors remain to be identified.
After excluding the influence of the three DPMs, significant linkage of IBD1 to CD in Jews remained with two peaks at D16S403 (mean allele sharing [MAS] = 0.70] and D16S411 (MAS = 0.59).