Disease relevance of NOD2

• These variants alter transcription and transporter functions of the organic cation transporters and interact with variants in another gene associated with Crohn disease, CARD15, to increase risk of Crohn disease [1].
• Here we examine the contribution of this susceptibility haplotype alone and in combination with CARD15 variants to CD subphenotypes and to susceptibility to ulcerative colitis (UC) [2].
• BACKGROUND & AIMS: Three years after the identification of NOD2/CARD15, 2 more genes for inflammatory bowel diseases (IBDs) were reported [3].
• 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 [2].
• In a previous study, a Crohn's disease gene, CARD15, was demonstrated to be associated with psoriatic arthritis (PsA) [4].
• Patients with Crohn's disease and unaffected relatives carrying variants of the NOD2 gene have increased adaptive immune responses to microbial antigens [5].
• The classic Blau syndrome/early-onset sarcoidosis triad of skin rash, arthritis, and recurrent uveitis was identified in 5 patients (41.7%), whereas 7 patients (58.3%) presented with fewer than 3 of the classic features [6].
• NOD2 genotyping may help predict disease progression in patients with Blau syndrome/EOS [7].

Psychiatry related information on NOD2

• Evaluations included self-assessment and physician's assessment of well-being, functional capacity, general clinical response, clinical activities indices (National Foundation for Ileitis and Colitis/International Organization for the Study of Inflammatory Bowel Disease and Harvey-Bradshaw), and achievement of specific therapeutic goals [8].
• Inflammatory bowel disease in children and adolescents: mental health and family functioning [9].
• The association between the use of passive coping strategies to deal with pain and reported levels of anxiety, depression, and parental reinforcement of illness behavior was examined in individuals with Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD) [10].
• Inflammatory bowel disease, acid peptic diseases, and intestinal motility disorders such as achalasia may mimic eating disorders [11].
• METHODS: A total of 120 individuals, 60 with ulcerative colitis and 60 with Crohn's disease, filled out the Inflammatory Bowel Disease Questionnaire, the Rosenberg Self-Esteem Scale, the Neuroticism scale of the Eysenck Personality Inventory, and a scale about difficulty describing feelings to other people [12].

High impact information on NOD2

• These results suggest that SLC22A4, SLC22A5 and CARD15 act in a common pathogenic pathway to cause Crohn disease [1].
• We found a significant difference in association of the 113A DLG5 variant with Crohn disease in affected individuals carrying the risk-associated CARD15 alleles versus those carrying non-risk-associated CARD15 alleles [13].
• We have identified three missense mutations in the nucleotide-binding domain (NBD) of CARD15/NOD2 in four French and German families with Blau syndrome [14].
• Inflammatory bowel disease, psoriasis, and complement [15].
• A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease [16].

Chemical compound and disease context of NOD2

• A missense mutation in the leucine-rich region of CARD15 is associated with gastric lymphoma [17].
• In contrast, overexpression of NOD2 containing the 3020insC frame-shift mutation, the most frequent NOD2 variant associated with Crohn disease, resulted in defective induction of hBD-2 through MDP [18].
• No relationship was found in general between the extraintestinal manifestations of Crohn's disease and smoking habits, previous Crohn's disease-related surgery, a family history of Crohn's disease, steroid resistance and CARD15 mutations [19].
• BACKGROUND & AIMS: The NOD2 gene, which is strongly associated with susceptibility to Crohn's disease (CD) of the terminal ileum, interacts with bacterial lipopolysaccharide (LPS), inducing cellular activation [20].
• Inflammatory bowel disease associated with levamisole and fluorouracil chemotherapy for colon cancer [21].

Biological context of NOD2

• The risk haplotype showed only a suggestive association with CD in the Jewish subgroup and no association with UC in the cohort or in subgroups stratified by CARD15 genotypes [2].
• We investigated associations with disease susceptibility, phenotype, and evidence for epistasis with CARD15 in 679 patients with Crohn's disease (CD) or ulcerative colitis (UC) [22].
• CONCLUSIONS: The SLC22A -TC haplotype acts together with CARD15 disease susceptibility alleles to increase risk for CD and ileal disease among CD patients but does not contribute to risk for UC in this Canadian cohort [2].
• Finally, this analysis shows that CARD15 involvement with CD is detectable by use of publicly available SNPs alone [23].
• CARD15 is related to the NOD1/Apaf-1 family of apoptosis regulators, and three sequence variants (Arg702Trp, Gly908Arg, and Leu1007fsinsC) in the gene were demonstrated to be associated with CD [23].

Anatomical context of NOD2

• The identification of the role of genetic variants within NOD2 (CARD15) in Crohn's disease and ulcerative colitis susceptibility highlight the role of the innate immune system in inflammatory bowel disease (IBD) pathogenesis [24].
• Recently, two members of a novel class of pattern recognition receptors, the cytosolic proteins nucleotide-binding oligomerization domain 1 (Nod1)/CARD4 and Nod2/CARD15, have been found to detect cell wall peptidoglycans [25].
• Microbial induction of CARD15 expression in intestinal epithelial cells via toll-like receptor 5 triggers an antibacterial response loop [26].
• In this work we aimed to analyze enterocyte NOD2/CARD15 expression and regulation in response to bacterial motifs and the consequences of the most common CD-specific CARD15 mutation on antibacterial responses of normal intestinal epithelial cells (IEC) [26].
• The CARD15 2936insC mutation and TLR4 896 A>G polymorphism in African Americans and risk of preterm premature rupture of membranes (PPROM) [27].

Associations of NOD2 with chemical compounds

• Despite observed differences in TNF production in mucosal biopsy tissue, there was no relationship between the overall presence of a mutation in NOD2/CARD15 or of any of the mutations separately and short-term infliximab response or response duration [28].
• Nod2 (CARD15) is a macrophage-specific protein containing two CARD domains, a large nucleotide binding domain and leucine-rich repeats [29].
• IEC transfected with the Crohn-specific CARD15 mutant (F3020insC, FS) failed to activate NFkB after MDP-challenge, in contrast to CARD15WT IEC [26].
• METHODS: In a geographic area in Southern Italy with high incidence of CD we investigated IP (lactulose/mannitol testing) together with the three main mutations of the NOD2/CARD15 and the D299G polymorphism of the toll-like receptor (TLR)-4 gene in 23 families of CD patients (patients and first-degree relatives) [30].
• A recently described mutation (2936insC) in CARD15 and a polymorphism in TLR4 896 A>G impair responses to LPS [27].
• A serological dosage effect was also observed. gASCA and AMCA antibodies were associated with NOD2/CARD15, in addition to a gene-dosage effect [31].

Physical interactions of NOD2

• The IBD6 Crohn's disease locus demonstrates complex interactions with CARD15 and IBD5 disease-associated variants [32].
• Nod2 interacted with the serine-threonine kinase RICK via a homophilic CARD-CARD interaction [33].
• Nod2 appears to interact with TAK1 through its LRR region to exert its inhibitory effect on TAK1-induced NF-kappaB activation [34].
• In addition, a change in the dynamics of the Erbin/Nod2 complex was observed during Shigella flexneri infection [35].
• The recognition of peptidoglycan by cells of the innate immune system has been controversial; both TLR2 and nucleotide-binding oligomerization domain-2 (NOD2) have been implicated in this process [36].

Co-localisations of NOD2

• CENTB1 partially co-localized with NOD2 and NOD1 proteins in the cytoplasm of mammalian cells [37].

Regulatory relationships of NOD2

• RESULTS: TNF-alpha induced an up-regulation of NOD2 in epithelial cell lines (HT-29, SW620, SW948, HeLa S3) and in primary colonic epithelial cells [38].
• Normal responses to specific NOD1-activating peptidoglycan agonists in the presence of the NOD2 frameshift and other mutations in Crohn's disease [39].
• Together, these data suggest that NOD2 serves as an intracellular pattern recognition receptor to enhance host defense by inducing the production of antimicrobial peptides such as hBD-2 [18].
• Suppression of the mRNA expression of nucleotide-binding oligomerization domain (NOD)1 and NOD2 by RNA interference specifically inhibited the synergistic IL-8 secretion induced by DMP and MDP with these TLR agonists respectively [40].
• The dominant negative form of TAK1 abolished muramyl dipeptide-induced NF-kappaB activation in Nod2-expressing cells [34].
• We also show that NOD2 promotes the membrane recruitment of RICK, a serine-threonine kinase involved in NF-kappaB activation downstream of NOD2 [41].

Other interactions of NOD2

• A higher frequency of DLG5 113A was observed in CARD15-positive patients (12.2%) compared with CARD15-negative patients (8.7%; P = .033) [3].
• Multipoint non-parametric linkage analyses were performed, with further stratification of affection status by common CARD15 mutations and the IBD5 haplotype [32].
• Evidence for linkage to chromosome 19 (IBD6) was observed in Crohn's disease pairs not possessing CARD15 mutations (P=0.0001), and in pairs possessing one or two copies of the IBD5 risk haplotype (P=0.0005), with significant evidence for genetic heterogeneity and epistasis, respectively [32].
• Because CARD4/NOD1 shares many structural and functional similarities with CARD15, we tested its putative role in IBD [42].
• We did not find a significant correlation between granulomas and TLR4 or CARD15 variants [43].

Analytical, diagnostic and therapeutic context of NOD2

• The healthy father and brother were CARD15 R702W positive, were non-smokers and had not undergone appendectomy [44].
• 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 [45].
• METHODS: Expression of NOD2 messenger RNA was determined by reverse-transcription polymerase chain reaction (RT-PCR); NOD2 protein was detected by Western blot [38].
• DNA was screened for possible NOD2/CARD15 mutations by denaturing high-performance liquid chromatography (confirmed by direct sequencing) [46].
• In vitro analyses revealed a dual biologic effect of TRAIL on HIEC: Under noninflammatory conditions, TRAIL up-regulated via nuclear factor-kappaB CARD15 and IL-8, whereas, under inflammatory conditions, TRAIL became a potent inducer of apoptosis in HIEC, which was confirmed ex vivo using ileal organ cultures [47].

References