Stanford Community Symposium 2018: Phair, Metabolic traps, Tryptophan trap

Random thought I've just had, and apologies if it has been covered already, I'm as much thinking out loud here as anything else.

So as I understand it, in very simplistic terms, @RDP is seeing the gene mutations in every single severe patient that they have tested, yet @Chris Ponting is reporting that the data from the UK Biobank shows these mutations as being rare, even in those who self-report a diagnosis of ME/CFS.

The thoughts that occur to me though are that
1. we know that ME/CFS diagnoses in the UK have been found to have a high error rate (up to 40%, if I remember correctly), so there is the potential for the occurrence of these mutations to be "diluted".
and 2. if the mutations are related to severity in some way, then the chance of those people with the mutations being included in the Biobank data is reduced as donors had to travel to central locations in order to have their samples taken - something which would make it less likely that someone with more severe ME/CFS would be a donor.

I think that makes sense? And, if so, that means that it shouldn't be so surprising to see the difference between the Stanford and the Biobank results. Let me know what I've got wrong.. :)
 
I'm beginning to think that GWAS isn't so great when there are multiple damaging mutations that are very common in the population in one particular gene. Combine that with what @Andy posts above and you are left with inconclusive data.

I may be wrong, but the more I look at actual data the more confusing things get for me regarding GWAS. @Simon M recently posted an article that GWAS is helpful in Schizophrenia. So when I saw this about a Broad Institute presentation I thought, good-oh, now I can use the UK Biobank web tool to see the same thing.


Someone pointed out the paper the slide was based on. So even better, I have actual locations to compare with a UK Biobank cohort for Schizophrenia to confirm how brilliant the UK Biobank GWAS tool is, the same one that showed IDO2 as not relevant for ME/CFS.


Yet the key thing highlighted in the paper and the presentation (first tweet above) is NOT present in the UK Biobank cohort.


And the elevated significance in the C4 region that is one of the major findings in the paper is NOT shown in the UK Biobank data


So what does this all mean..... probably that I should leave it to the experts to get on with their research.
 
@wigglethemouse, doesn't the same thing apply re. schizophrenia and donations to the Biobank as with severe ME?

I have two schoolfriends who developed it whilst in higher education in the late 1970s; both still live difficult and sometimes chaotic lives, with periods of significant illness. Neither has managed to find employment or achieve long-term stability, despite being prodigiously talented and having committed families and friends who make great efforts to support them.

A proportion of patients do live well with schizophrenia, but there must be many others who're as unlikely to engage with a project like the Biobank as a severe ME patient.
 
wigglethemouse said:
I'm beginning to think that GWAS isn't so great when there are multiple damaging mutations that are very common in the population in one particular gene. Combine that with what @Andy posts above and you are left with inconclusive data.
Click to expand...

I think it's very important that researchers are careful about who they use to sample. They have to be 100% certain they have the disease.. especially with diseases which are not diagnosed using biological tests, such as ME or mental health problems.

I agree, the Biobank's data will be wrong if the patients are using the UK method for diagnosing ME, and completely useless if a member of the public can self diagnose.

I mean the internet is plastered with people who self diagnosed ME and were suddenly cured after removing a filling or quiting gluten.. They probably had celiac disease or something, we just don't know.
 
wigglethemouse said:
I'm beginning to think that GWAS isn't so great when there are multiple damaging mutations that are very common in the population in one particular gene. Combine that with what @Andy posts above and you are left with inconclusive data.

I may be wrong, but the more I look at actual data the more confusing things get for me regarding GWAS. @Simon M recently posted an article that GWAS is helpful in Schizophrenia. So when I saw this about a Broad Institute presentation I thought, good-oh, now I can use the UK Biobank web tool to see the same thing.


Someone pointed out the paper the slide was based on. So even better, I have actual locations to compare with a UK Biobank cohort for Schizophrenia to confirm how brilliant the UK Biobank GWAS tool is, the same one that showed IDO2 as not relevant for ME/CFS.


Yet the key thing highlighted in the paper and the presentation (first tweet above) is NOT present in the UK Biobank cohort.


And the elevated significance in the C4 region that is one of the major findings in the paper is NOT shown in the UK Biobank data


So what does this all mean..... probably that I should leave it to the experts to get on with their research.
Click to expand...


Thanks. The reason that it doesn't show up in the UK Biobank (UKBB) is that this UKBB project was not focused on a particular disease (e.g. schizophrenia) but instead recruited 500,000 people from across the UK of whom relatively few had a schizophrenia diagnosis. The power of a GWAS comes from encouraging large numbers of individuals with the *same diagnosis* to allow comparison of their DNA changes to those from the general population (a "case-control comparison"). This is how the schizophrenia GWAS were performed in the first place. We are planning a large ME/CFS case-control GWAS. Hope this helps.
 
Posted on PR by Robert Phair—not a private thread.

https://forums.phoenixrising.me/thr...rse-on-l-tryptophan.84658/page-6#post-2355481

“As others in this thread have said, the role of serotonin in ME/CFS remains unsettled, but I can at least say what is predicted for any cell type in the IDO metabolic trap.

First, let's consider an immune system cell that has all the enzymes of the kynurenine pathway, but does not express the enzymes of the serotonin pathway. Here, you can get into the trap and all the consequences will be caused by the failure to make kynurenine, and ultimately the failure to make NAD. Failure to make NAD strikes many people as important because you need NAD to run central carbon metabolism and make ATP, but if you are getting plenty of niacin in your diet, then NAD produced from Trp is probably not essential. To me, the main danger of the trap is the absence of kynurenine, which normally activates the ligand-activated AHR transcription factor. Hence, all the genes that are normally turned on by an active kynurenine pathway, are turned off. I've also considered that the high cytosolic Trp might drive the mTOR amino acid sufficiency pathway, but that's another story.

Now, let's switch to the serotonergic neurons in the brainstem. These cells, to the best of our knowledge, express both the kynurenine pathway and the serotonin pathway, and as you know, Trp is the first substrate in both pathways. In cell types with both pathways, you not only fail to make kynurenine, but you have further consequences of high intracellular Trp. In particular, you will be maximizing the production of 5-hydroxytryptophan by the enzyme TPH2. This could result in substantially greater serotonin synthesis so that a supplemental dose of 5-hydroxytryptophan could be all you need to get into a serotonin syndrome-like situation. Some scientists think this is actually inconsistent with ME/CFS, but I think it's true that many patients have horror stories around SSRIs, tryptophan, and 5-hydroxytryptophan so I have not ruled this out. Serotonergic neurons project to many parts of brain that are potentially responsible for major CFS symptoms. We can make a plausible case, but as yet we cannot prove these things are happening in CFS brains.

When you think about the trap, please always think about a specific cell type. The events of the trap are taking place inside the cell and it is unlikely that the affected cell type can produce the same changes in the extracellular space or in blood plasma that it produces inside the cell. For example, there are about 10,000 serotonergic neurons in the brainstem, but there are about 1E11 neurons in the brain. That's seven orders of magnitude difference, so even if all 10,000 serotonergic neurons are trapped, there is absolutely no chance you would detect this in cerebrospinal fluid if all the rest of the neurons are making their normal kynurenine, People argue the theory cannot be right because we do not see high Trp and low Kyn in plasma of CFS patients, but those people are assuming that every body cell or at least a large number of body cells is in the trap. I admit it's much harder to test a theory whose mechanism is confined to one cell type, especially if that cell type is a minority cell type, but you will see immediately that if the affected cell type was a majority cell type like skeletal myocytes, we would probably have found a biomarker years ago. To me, the absence of a reliable plasma biomarker, after all these years, is a hint that we should be looking for malfunction of a minority cell type that is part of an important physiological control system.

Our concern about Trp supplements is not about the fate of trapped cells; we are just worried that you could push more cells into the trap and make the disease worse. 5-hydroxytryptophan supplements are even harder to evaluate because cells expressing TPH2 will already be making too much serotonin, but cells expressing TPH1 (which is also substrate inhibited by high Trp, like IDO1) like gut and pineal will be making too little serotonin.

I've written many words here. Hopefully, I've shed some light on the questions posed in this thread. I'm sorry it's so complicated, but no one is arguing that CFS is simple.”
 
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