Recent work has consistently shown XIAP to be critical for signaling downstream of the Crohn's disease susceptibility protein nucleotide-binding oligomerization domain-containing 2 (NOD2); however, the reported effects of XLP-2 and VEO-IBD XIAP mutations on cell death have been inconsistent.
Our aim was to ascertain the contribution of OCTN variants to UC and CD in a large independent UK dataset, to seek genetic evidence that the OCTN association is distinct from the IBD5 risk haplotype and to identify interactions between the IBD5 and CARD15 loci.
The development of Crohn's disease in a previously normal patient receiving an allogeneic transplant from an individual with the NOD2 mutation illustrates the importance of the genotype of the immune system.
Defining these NOD2-regulated responses, and how mutations in the gene encoding this protein disrupt these responses, will be key to understanding the pathogenesis of Crohn's disease.
Thus, NOD2 mediates the host response to bacterial muropeptides derived from peptidoglycan, an activity that is important for protection against Crohn's disease.
Genotyping included CARD15/NOD2 variants p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008 and polymorphisms in SLC22A4/OCTN1 (1672 C-->T) and SLC22A5/OCTN2 (-207 G-->C) as well as 10 CD-associated IL23R variants.
The nucleotide oligomerization domain 2/caspase activating recruitment domain 15 gene (NOD2/CARD15) is the most well-established gene to be associated with increased susceptibility to Crohn's disease.
Recent genome scans and replication studies have identified replicated linkage between CD and a locus on chromosome 16 (the IBD1 locus), replicated linkage between IBD (especially UC) and a locus on chromosome 12q (the IBD2 locus), and replicated linkage between IBD (especially CD) and a locus on chromosome 6p (the IBD3 locus).
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.
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.
The aims of the study were to replicate the association with CD, examine subphenotype associations and statistical interactions with CARD15, IL23R, and the IBD5 risk haplotype, as well as explore the association with UC.
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.
These results implicate NOD2 in susceptibility to Crohn's disease, and suggest a link between an innate immune response to bacterial components and development of disease.