NOD2: A Common pathway that may be disrupted in ME/CFS

kday

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I'm putting this out there so hopefully researchers and others can look into this information to verify my claims.

I have looked through 23 23andMe ME/CFS genomes as well as 3 WGS genomes.

There is a common thread. NOD2 mutations seem to have greatly increased prevalence.

In fact, all 3 WGS samples (100%) have deleterious mutations in NOD2. The first genome has 2 verified pathogenic mutations. The second genome has a single extremely rare predicted damaging variant. And the third genome has two verified pathogenic NOD2 mutations as well as an extremely rare predicted damaging variant (a total of 3 variants). The pathogenic NOD2 mutations were all confirmed with corresponding 23andMe data. And when it comes to 23andMe data, 47.8% of 23 ME/CFS raw data files had a rare and not very common VERIFIED pathogenic mutation. For WGS data specifically, some are predicted by Variant Effect Predictor or Mutation Taster and others are established variants in the NCBI/NIH ClinVar database. 23andMe has some of the important NOD2 variants. But in two WGS samples, there are also predicted NOD2 mutations that are EXTRAORDINARILY rare. The very rare alt allele frequencies were confirmed with gnomAD browser, so they appear to be real variants. The NOD2 mutations range from not very common to rare, but seem to be very common in ME/CFS genomes. And the 23andMe data is self-reported publicly accessible data. So they may be even more common in patients that are verified by ME/CFS expert clinicians. And you need Whole Genome Sequencing to look at the very rare NOD2 damaging variants that I am seeing!

NOD2 is associated with Crohn's Disease, IBD/IBS, and other Autoinflammatory conditions. It's even associated with Fibromyalgia, but no study has been done on NOD2 and it's relationship to ME/CFS. I believe recent GWAS studies completely missed this as well.

NOD2 is important for the recognition and immune response to ssRNA viruses (e.g. Coxsackievirus is an ssRNA virus but herpes viruses are not) and Peptidoglycans (which is a component of the cell wall for almost all bacteria).

I think this is important because what if ME/CFS is an autoinflammatory illness initiated or perpetuated by dysregulation of the NOD-like receptor signaling pathway? What if this could create another negative feedback loop? And most importantly, what if targetted treatments could help ME/CFS symptoms?

Of course, research needs to be done first. This post serves as a call to action for researchers that browse this forum. But to summarize my findings, 100% of ME/CFS Whole Genome Sequence VCF files contained pathogenic and very rare predicted damaging mutations, and 47.8% of 23andMe ME/CFS genomes had pathogenic NOD2 variants that are listed in OMIM.

KEGG NOD-like receptor signaling pathway:
https://www.genome.jp/kegg-bin/show_pathway?ko04621+K10165
 

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kday

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This part is just a theory. But it seems like with NOD2 mutations, the gut isn't particularly good at clearing the harmful microbes and potential overgrowth.

Many chemicals and substances (as well as infections) actually upregulate NOD2. But the chemical 1,3-Butadiene in particular (as well as BPA) downregulates this enzyme and reduces expression of NOD2. What impact can such a common chemical have on an enzyme that may be not working very well in the first place?

1,3-Butadiene is in wood smoke, tobacco smoke, plastics/rubbers, vehicle exhaust, and even contaminated drinking water. Tests aren't available for testing the toxicity of this compound. I don't know if the NOD2 enzyme could be linked to the observed chemical sensitivity, but I find it very interesting that this common chemical decreases the expression of an enzyme that's very important for virus and bacteria recognition and defense.
 
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kday

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There is a 2019 study out of Taiwan that makes a connection between Inflammatory Bowel Disease and increased risk of CFS.

Increased risk of chronic fatigue syndrome in patients with infammatory bowel disease: a population-based retrospective cohort study

http://sci-hub.tw/https://doi.org/10.1186/s12967-019-1797-3

Although the definite pathogenesis of IBD remains unclear, unusual intestinal immune reaction triggered by intestinal fora could lead to inflammation [22] or deficit in the intestinal barrier and bacterial translocation [23]. Noticeably, bacterial translocation has been also proposed as one of the mechanism underlying CFS [9]. This hypothesis could be evidenced by the fact that serum IgA levels against the Lipopolysaccharide (LPS) of enterobacteria were significantly higher in patients with CFS. A study demonstrated the peripheral inflammation is induced by the LPS via binding to the toll-like receptor-4 complex [24]. If there is a mutation of Nucleotide binding oligomerization domain 2 (NOD2), a protein that binds to the peptidoglycan of bacteria resulting in NF-κB activation and inflammatory response, it could lead to CD development [25]. NF-κB is associated with a subjective feeling of fatigue [26] and activation of this pathway is common in both IBD [27] and CFS populations. Moreover, pro-inflammatory cytokines signals could also be relayed to brain by the autonomic nervous system and activated microglia could result in neuroinflammation and increased cytokine levels in brain [28]. There is an association between increased brain Interferon-γ (IFNγ), levels and certain somatic traits such as fatigue and hyperalgesia [29]. The hypothesis of bacterial translocation from the gastrointestinal tract is illustrated as Fig. 3. However, the above hypothesis is one of the possible explanations. Dysbiosis of the gut microbiota and an increased incidence of microbial translocation were suggested to play a principal role in inflammatory symptoms in CFS [30]. Thus, microbiota-gut-brain interactions were indicated essentially in the clinical presentations of a subgroup of patients with CFS [31, 32].
While it doesn't look like this study specifically looked at the rate of NOD2 mutations in ME/CFS, it looks like NOD2 may be an important avenue of research in regards to ME/CFS because of the overlapping pathophysiology of IBD and CFS.

Here's an illustration from the study showing the overlap:
Annotation 2019-07-19 144408.jpg
 
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Great job hypothesizing and looking at the data sets!!!

I'm a little kid, doubled over in the back seat of the car, intestinally distressed....all that occured BEFORE Eppstein Barr.

I just wish we could FIX something, soon, please.:sluggish::sluggish: