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.
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.
New serological markers for inflammatory bowel disease are associated with earlier age at onset, complicated disease behavior, risk for surgery, and NOD2/CARD15 genotype in a Hungarian IBD cohort.
Reduction in alpha-defensin expression is independent of NOD2 status and is due to loss of surface epithelium as a consequence of inflammatory changes rather than being the inciting event prior to inflammation in ileal Crohn's disease.
This study confirms that CARD15 carriers, especially L1007fs mutants, in central Europeans have an increased risk of CD and it is associated with earlier onset, ileal, fibrostenotic disease and a higher risk of surgery.
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.
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).
The results of the study confirm a significant association of CARD15 gene mutations in our Italian Crohn's disease population and the impact of different NOD2/CARD15 mutations on specific disease phenotypes.
Polymorphisms 3020insC in CARD15 and SNP rs3792876 in SLC22A4/5 occurred statistically significantly more often in patients with pediatric-onset CD than in patients with adult-onset 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).
Under normal conditions, IEC lines and ileal enterocytes did not express NOD2/CARD15 mRNA or protein, contrary to IEC derived from inflammatory CD sections.
In non-Caucasian populations Crohn's disease continues to increase in incidence but this increase appears not to be a consequence of variation in NOD2, further advancing the accumulating evidence for other susceptibility loci.