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Schema Name NOD2 Schema for Crohn's disease
Accession MS020700043.2
Gene(s) NOD2
Schema Caption How mutation in NOD2 is linked to increased Crohn's disease risk
Schema Description NOD2 is one of the most important loci for Crohn's disease. NOD2 have been associated with susceptibility to ileal Crohn's disease with an odds ratio equal to 2.4 in heterozygote individuals and 17.1 in homozygotes or compound heterozygotes, representing the strongest association with CD to date (pmid: 15571588). The complexity of the disease, like stricturing or fistulizing, is increased by 8% for NOD2 heterozygotes and 41% for NOD2 homozygotes or compound heterozygotes and the risk of surgery is increased by 58% with any of NOD2 mutations (pmid:  21343918). Three main variants of NOD2 gene which are associated with Crohn's disease risk, are one frameshift mutation - L1007fsC (rs2066847), and two missense SNVs - R702W (rs2066844) and G908R (rs2066845) (pmid:  11385577,  11385576,  11875755). We start this mechanism schema with the frameshift single base insertion at 1007 position (rs2066847) which is the strongest disease predictive factor. In this schema, we address the role of this frameshift mutation in increased inflammation, reduced microbial clearance and reduced xenophagy which are characteristics of Crohn's disease phenotypes.
Author(s) Lipika R. Pal, Kunal Kundu, Lindley Darden and John Moult
Curator(s) Lipika R. Pal, John Moult
Last Modified Fri Aug 10 2018 15:47:03 GMT-0400 (Eastern Daylight Time)
Sub-state Perturbation (SSP) Annotations
Component ID: SSP1
Stage: DNA
SSP Class: Other
Other SSP Class: IN/DEL [HET/HOM]
Modifier: NA
Ontology:
SSP Instance: rs2066847 in NOD2
Confidence Score: 5
Comment: SNPs in NOD2 have been associated with susceptibility to ileal CD with an odds ratio equal to 2.4 in heterozygote individuals and 17.1 in homozygotes or compound heterozygotes, representing the strongest association with CD to date [pmid: 15571588]. The complexity of the disease, like stricturing or fistulizing, is increased by 8% for NOD2 heterozygotes and 41% for NOD2 homozygotes or compound heterozygotes and the risk of surgery is increased by 58% with any of NOD2 mutations [pmid: 21343918]. Three main variants of NOD2 gene which are associated with CD risk, are a frameshift mutation - L1007fsC (rs2066847), and two missense SNVs - R702W (rs2066844) and G908R (rs2066845) [pmid: 11385577, 11385576, 11875755]. We start this mechanism schema with the frameshift single base insertion at 1007 position (rs2066847) which is the strongest disease predictive factor.
For Evidence: PMID:15571588, PMID:18824555
Against Evidence:
Component ID: SSP2
Stage: RNA
SSP Class: mRNA Abundance
Other SSP Class:
Modifier: NA
Ontology:
SSP Instance: NM_022162: c.1007insC
Confidence Score: 5
Comment:
For Evidence:
Against Evidence:
Component ID: SSP3
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Decreased
Ontology: PLOSTHES
SSP Instance: NOD2
Confidence Score: 5
Comment: NMD implies less protein product at the Protein stage.
For Evidence: PMID:26500656
Against Evidence:
Component ID: SSP4
Stage: Complex
SSP Class: Protein-Protein Complex Abundance
Other SSP Class:
Modifier: Decreased
Ontology:
SSP Instance: NOD2-RIP2
Confidence Score: 5
Comment: Due to NMD, there will be less protein complex with RIP2.
For Evidence: PMID:28253332, PMID:26500656
Against Evidence:
Component ID: SSP5
Stage: Cell
SSP Class: Other
Other SSP Class: Regulatory Effect
Modifier: Decreased
Ontology:
SSP Instance: Negative regulation of TLR2 signaling
Confidence Score: 3
Comment: There is evidence from the mouse model that NOD2 is acting as inhibitor of TLR2 signaling [pmid: 15282558, 15220916]. However, in human cell line, a synergistic effect is observed, where this interaction is MDP dose dependent [pmid: 18340358]. This ambiguity leads to medium confidence color.
For Evidence: PMID:15282558, PMID:15220916
Against Evidence: PMID:18340358
Component ID: SSP6
Stage: Cell
SSP Class: Other
Other SSP Class: Cell Product Abundance
Modifier: Increased
Ontology:
SSP Instance: Pro-inflammatory Cytokines, IL-12
Confidence Score: 5
Comment: Pro-inflammatory cytokines are more due to activated NF-kB pathway.
For Evidence:
Against Evidence:
Component ID: SSP8
Stage: Cell
SSP Class: Other
Other SSP Class: Cell Product Abundance
Modifier: Decreased
Ontology:
SSP Instance: Pro-inflammatory Cytokines
Confidence Score: 3
Comment: Less pro-inflammatory cytokine production due to deactivated NF-kB and MAPK signaling pathway.
For Evidence: PMID:28253332
Against Evidence:
Component ID: SSP9
Stage: Cell
SSP Class: Other
Other SSP Class: Cell Product Abundance
Modifier: Decreased
Ontology:
SSP Instance: Defensins in Paneth cell
Confidence Score: 3
Comment: Deactivation of NF-kB pathway also leads to less defensin in the Paneth cell (SSP9) [pmid: 19079235]. However, there is some contradiction whether lower defensin level in Crohn’s patients is dependent on NOD2 mutation or not [pmid: 18305068] – resulting into medium confidence color for SSP9.
For Evidence: PMID:19079235
Against Evidence: PMID:18305068
Component ID: SSP7
Stage: Cell
SSP Class: Other
Other SSP Class: Adaptive Immune Response
Modifier: Altered
Ontology:
SSP Instance: Lack of Th2 type response from CD4+ helper T cell
Confidence Score: 5
Comment: Adaptive immune response gets activated, leading to lack of Th2 type responses from CD4+ helper T cell.
For Evidence: PMID:19017983
Against Evidence:
Component ID: SSP14
Stage: Phenotype
SSP Class: Other
Other SSP Class: Disease Risk
Modifier: Increased
Ontology:
SSP Instance: Crohn's with lower NF-kB level
Confidence Score: 5
Comment: Crohn's patient with lower NF-kB level. NOD2 may function to both positively and negatively attenuate NF-kB signaling; thus, NOD2's function may depend on the circumstance surrounding its activation.
For Evidence: PMID:15620648
Against Evidence:
Component ID: SSP15
Stage: Phenotype
SSP Class: Other
Other SSP Class: Disease Risk
Modifier: Increased
Ontology:
SSP Instance: Crohn's with higher NF-kB level
Confidence Score: 5
Comment: This excessive inflammation with higher NF-kB level leads to severe form of CD.
For Evidence: PMID:28753650
Against Evidence:
Component ID: SSP16
Stage: Phenotype
SSP Class: Other
Other SSP Class: Disease Risk
Modifier: Increased
Ontology:
SSP Instance: Colorectal cancer
Confidence Score: 5
Comment: When this inflammation becomes chronic, this effect turns to colorectal cancer.
For Evidence: PMID:19887045, PMID:28658623
Against Evidence:
Component ID: SSP10
Stage: Complex
SSP Class: Protein-Protein Complex Abundance
Other SSP Class:
Modifier: Decreased
Ontology:
SSP Instance: NOD2-ATG16L1
Confidence Score: 5
Comment: Due to NMD, there will be less protein complex with ATG16L1.
For Evidence: PMID:20637199
Against Evidence:
Component ID: SSP11
Stage: Complex
SSP Class: Protein-Ligand Complex Abundance
Other SSP Class:
Modifier: Decreased
Ontology:
SSP Instance: NOD2-MDP
Confidence Score: 5
Comment: Due to NMD, there will be lack of NOD2 and MDP binding.
For Evidence: PMID:24336102, PMID:26500656
Against Evidence:
Component ID: SSP12
Stage: Cell
SSP Class: Other
Other SSP Class: Pathogen Abundance
Modifier: Increased
Ontology:
SSP Instance: Bacteria in epithelial cell
Confidence Score: 5
Comment: Less defensin production in Paneth cell, reduced xenophagy and lack of bacterial cell-wall recognition – all are leading to one event – excess load of bacteria in the epithelial cell (SSP12).
For Evidence:
Against Evidence:
Component ID: SSP13
Stage: Phenotype
SSP Class: Other
Other SSP Class: Disease Risk
Modifier: Increased
Ontology:
SSP Instance: Ileal Crohn's disease
Confidence Score: 3
Comment: Excessive bacterial translocation is leading to Ileal CD for NOD2 mutations [pmid: 27703457]. However, this is not clearly understood that why NOD2 mutations are leading to only Ileal CD (as opposed to colonic one) – what type of mechanisms are operative here that is not known yet, resulting into the medium confidence color (orange) for SSP13.
For Evidence: PMID:27703457
Against Evidence:
Biomarker(s) Annotations
Mechanism Module (MM) Annotations
Component ID: MM1
Mechanism Class Name: Transcription Rate
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment:
For Evidence:
Against Evidence:
Component ID: MM3
Mechanism Class Name: Le Chatelier
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Effect of chemical equilibrium.
For Evidence:
Against Evidence:
Component ID: MM2
Mechanism Class Name:
Other Mechanism Class Name: Nonsense mediated decay
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment: The frameshift implies nonsense-mediated decay (NMD) at the RNA stage, but there is no direct evidence for that, hence the medium confidence color (orange) here.
For Evidence:
Against Evidence:
Component ID: MM4B
Mechanism Class Name:
Other Mechanism Class Name: Deactivation of NF-kB, MAPK signaling
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment: Less NOD2-RIP2 complex is supposed to be followed by deactivated NF-kB pathway and reduced MAPK signaling – resulting into less cytokine production (SSP8) [pmid: 28253332] and consequently less inflammation (MM8) for Crohn’s patients. However, there is evidence of Crohn’s patients with higher levels of NF-kB proteins [pmid: 15620648]. Discrepancy in this observation is leading towards ‘OR’ branching of mechanism modules coming out from SSP4 and medium confidence color (orange) for MM4B and SSP8.
For Evidence: PMID:28253332
Against Evidence:
Component ID: MM5
Mechanism Class Name:
Other Mechanism Class Name: Activation of NF-kB pathway
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: When there is defect in the inhibitory role for NOD2, TLR2 signaling gets activated, leading to activation of NF-kB pathway [pmid: 15282558] and more production of cytokines or chemokines.
For Evidence: PMID:15282558
Against Evidence:
Component ID: MM8
Mechanism Class Name:
Other Mechanism Class Name: Inflammation
Modifer: Decreased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Decreased inflammation due to decreased abundance of pro-inflammatory cytokines.
For Evidence:
Against Evidence:
Component ID: MM9
Mechanism Class Name:
Other Mechanism Class Name: Bacterial removal
Modifer: Decreased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Lower defensin level at the paneth cell will lead to decreased removal of bacteria.
For Evidence:
Against Evidence:
Component ID: MM7
Mechanism Class Name:
Other Mechanism Class Name: Inflammation
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Excessive inflammation for Crohn's patients.
For Evidence:
Against Evidence:
Component ID: MM10
Mechanism Class Name:
Other Mechanism Class Name: Xenophagy
Modifer: Decreased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Decreased abundance of NOD2-ATG16L1 complex leads to reduced xenophagy.
For Evidence: PMID:19966812, PMID:25497060
Against Evidence:
Component ID: MM11
Mechanism Class Name:
Other Mechanism Class Name: MDP recognition by NOD2
Modifer: Decreased
Ontology: NCIT
Mechanism Instance:
Confidence Score: 5
Comment: Due to NMD, there will be less recognition of bacterial cell wall by NOD2.
For Evidence: PMID:24336102
Against Evidence:
Component ID: MM12
Mechanism Class Name:
Other Mechanism Class Name: Bacterial translocation
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Excessive bacterial translocation is leading to Ileal CD for NOD2 mutations [pmid: 27703457].
For Evidence: PMID:27703457
Against Evidence:
Component ID: MM6
Mechanism Class Name:
Other Mechanism Class Name: IFN-γ production
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: When IL-12 pro-inflammatory cytokines will be activated, more IFN-gamma will be produced which is coming from Th-1 type cytokine response.
For Evidence: PMID:9505196
Against Evidence:
Unknown Mechanism Module (MM) Annotations
Component ID: MM4A
Comment: It is not very clear yet, how NOD2 is playing the inhibitory role for TLR2 – we used a blackbox here. There is some suggestion that this interaction is also controlled by RIP2 complex [pmid: 11894098, 16227353].
For Evidence: PMID:11894098, PMID:16227353
Against Evidence:
Environmental Factor Annotations
Therapeutic Interventions Annotations