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IDO2 gene mutations - SNPs

Discussion in 'BioMedical ME/CFS Research' started by daftasabrush, Dec 20, 2019.

  1. daftasabrush

    daftasabrush Senior Member (Voting Rights)

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    Background
    The metabolic trap hypothesis being investigated by the OMF is currently investigating IDO2, with the Severely Ill Big Data Project finding IDO2 mutations in the 20 patients ill with M.E.
    This question is about how someone can check if they have the mutations found based on genetic data analyzed by popular saliva tests.

    Gene data
    Many people have had their genetic data analyzed from saliva tests, eg by 23andMe or Ancestry DNA. This results in a large file that can be searched for different SNPs. Various projects have collected this data eg Nova Southeastern's ME/CFS Gene Study run by Nancy Klimas.

    Question 1
    I believe 5 or 6 IDO2 mutations were identified, that meant IDO2 was either not working at all or not working properly.
    How can you find a list of these to compare with you own genetic data?
    What seems to be needed is the rsid and the corresponding allele values.

    Source 1:
    The diagram on p5 may contain part of the answer, but what exactly to look for in the file?
    https://www.omf.ngo/wp-content/uploads/2018/11/Edited-Robert-Phair-Metabolic-Trap.pdf

    Source 2:

    Diagnostics 2019, 9(3), 82; https://doi.org/10.3390/diagnostics9030082
    The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS

    Table 1. Common and rare mutations in IDO2 identified as damaging 3.

    eg for mutation R248W -
    snp rs10109853
    Allele ref > alt C > T
    exon 9
    Min pop AF 0.418 (minimum alternate allele frequency (expressed as a fraction) reported [28] for any sampled population)
    Max pop AF 0.487 (maximum alternate allele frequency reported for any sampled population)
    SIFT damaging
    PROVEAN deleterious
    POLYPHEN probably damaging

    so with your genetic data, suppose it says:
    rsid rs10109853
    chromosome 1
    allele 1 G
    allele 2 G
    * how does this compare to the damaging mutation?
    *Do alleles 1 and 2 need to be any letter between C and T?
    *Does the exon need to match the chromosome number to have that mutation?
    *Are the min / max values relevant, or is that missing from the genetic data analysis?
    *Where to look for the R248W? Is this the name of a gene or something else?

    Question 2
    Are there any particular values that should be there, that would cause a problem in IDO2 if they are missing?

    Please forgive me for any basic misunderstandings or confusion and the many wrong words. I am extremely brain fogged and it's taken me so very long just to get this far.
     
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  2. Kitty

    Kitty Senior Member (Voting Rights)

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    The rsids are given at the top of the table you mention. They appear to be:

    rs10109853
    rs4503083
    rs4736794
    rs35212142
    rs774492001

    Not all of them will necessarily be reported in direct-to-consumer genetic testing.

    This means that the reference (more frequent) allele is C and the alternative (less frequent) is T. However, the so-called 'alternative' allele is still very common, appearing in between 41% and 48% of all sampled populations.

    This is one way of referring to a specific variant within a particular gene. It isn't always described this way in
    direct-to-consumer test reports – as you say, the rsid is easier to look for.

    This is about how the gene is 'read', or the orientation. Here's an article that might make this a bit easier to understand:

    https://www.snpedia.com/index.php/Orientation


    It's worth remembering that the metabolic trap is still only a theory at the moment. These mutation are described as 'damaging', but we don't know whether they actually have meaningful consequences. For instance, a variant might mean the body is only able to produce small amounts of a given enzyme, which can look important at first sight – but there could be compensating mechanisms elsewhere, which mean it has little or no effect on the body's ability to function normally.
     
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  3. Barry

    Barry Senior Member (Voting Rights)

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    @RDP said:
    This intrigues me, because the flux described here relates to molecule conversions per unit time. The biological pathways between this and pwME's energy utilisation is way above my head I'm afraid, but ultimately the energy limitation pwME primarily suffer from (I'm pretty sure) is energy availability per unit time - i.e. power.

    Does this IDO2 fault ultimately translate into a reduction in available power for pwME?

    upload_2019-12-20_13-44-52.png
     
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  4. daftasabrush

    daftasabrush Senior Member (Voting Rights)

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    I think I'm getting there, but a few more questions:

    1. are alleles T > C equivalent to C > T (ie does positive or negative matter)?

    2. can chromosome number be ignored, because the chromosome number either isn't important or would always be the same?
    (I noticed the gene mutations didn't state what chromosome each was found in)

    3. What is the exon, and does it further restrict whether a gene is matched? (ie if exon isn't reported in DNA results, does that mean only some of them will match)?

    4. What are the min / max values about?

    5. Finally, the research paper says Table 1. Common and rare mutations in IDO2 identified as damaging 3.

    So is a match to that table (potentially) damaging? Or is it saying that if you have those rsid numbers, and if your alleles are different to those in the table then only that is (potentially) damaging?
     
  5. Kitty

    Kitty Senior Member (Voting Rights)

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    I have to go out, but I'll do this one because it's fairly straightforward:

    The symbol '>' is used to indicate 'greater than'. So 9>8 just means 9 is more than 8.

    '<' means 'lesser than' in the same way.

    T>C usually indicates that more people in the sampled population have the T allele than the C.

    C>T usually indicates that more people in the sampled population have the C allele than the T.
     
  6. Barry

    Barry Senior Member (Voting Rights)

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    I don't know if the values in question can go negative or not, but if so then to be purist:

    8>-9 would be true of course. Unless for any negative quantities it were only their magnitudes that mattered, and not their sign.
     
  7. Barry

    Barry Senior Member (Voting Rights)

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    A few very elementary questions, but I'm interested.

    I emphasise this is purely hypothetical, as I imagine it would be extremely foolish and dangerous to try this in practice! So please don't!

    Given that humans cannot manufacture tryptophan and can only obtain it from foods, what would happen if someone were to eat a tryptophan-free diet? (i.e. Identical diet to normal except without the tryptophan - impossible in practice I imagine). Seeing as once in the trap the high tryptophan density is actually preventing its conversion to kynurenine, would there be much difference? Is @RDP saying that once the trap is fully established, then although the extra-cellular tryptophan density would drop, the intra-cellular tryptophan density would remain high? Is it the intra-cellular tryptophan density that is the key interest here?
     
  8. sb4

    sb4 Senior Member (Voting Rights)

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    Somebody over on PR did a very low / zero tryp diet and if I remember correctly didn't notice any improvements however I think he said he did notice worsening with high tryp foods.
     
  9. Trish

    Trish Moderator Staff Member

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    Trouble is tryptophan is an essential amino acid present in protein and I assume needed for most protein based cell structures and functions in the body, so deficiency sounds to me like a bad idea.
     
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  10. Barry

    Barry Senior Member (Voting Rights)

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    But from @RDP's talk tryptophan's primary benefit is it being converted to kynurenine, which is depleted anyway once in the IDO trap; the tryptophan in itself is of no use other than being converted to something else. Or am I missing something crucial here?

    But I do also see it gets converted to seratonin, which would suffer if no tryptophan were available.

    It was really a thought experiment, to try and understand if dropping the tryptophan concentration would pull the molecular conversion back into the IDO1 operating range, where conversion could still work within those limits, and out of the IDO2 operating range which is broken. But I think (but not at all sure) if this is where the 10 day / 8 week issue comes into play).
     
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  11. Trish

    Trish Moderator Staff Member

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    I may be the blind leading the blind here. I'm sure our biochemists could answer this better than I can, but as I understand it there are 20 essential amino acids, of which tryptophan is one.

    Amino acids bind together into complex structures to create proteins. Many of the structures in the body are proteins, for example actin and myosin, the two large molecules in muscles that make them contract, are proteins made from thousands of amino acids, including tryptophan. For example, google told me this:
    And this paper tells me myosin includes tryptophan.
    http://www.jbc.org/content/275/33/25481.full.html

    So my point was that tryptophan's role in the serotonin and kynurenine pathway is not its only role in the body. So we shouldn't try to deprive ourselves of it completely.
     
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  12. Barry

    Barry Senior Member (Voting Rights)

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    Which is why I say it was a thought experiment. I acknowledge I did not fully appreciate tryptophan had other important roles*, but in the context of this thought experiment it's of no consequence anyway, because no one is suggesting to do it for real at all ... I emphasised that right at the beginning.

    If this were an engineering system I could potentially just isolate the bits I was interested in testing, and not fuss with the other bits. But with real biology and real living people you clearly cannot do that, hence trying it as a thought experiment. Just pretending you could look at the IDO trap aspect in isolation, and saying if tryptophan concentration could be dropped to zero for just that bit of the biology, what would happen? I suspect that is what Robert Phair has already covered anyway, but I got lost along the way. Especially not understanding if it is only the intra-cellular tryptophan concentrations that are significant, and if after 8 weeks those stay stuck at high levels no matter what else you do.

    *Based on Robert Phair's comments: "There are other small or minor fates but big ones are the kynurenine pathway that goes from east to west in this diagram. ... just to make the system complete, there's a pathway going from north to south here that also is important for the fate of tryptophan and it is the production of serotonin")
     
    Last edited: Dec 22, 2019
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  13. Barry

    Barry Senior Member (Voting Rights)

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    As I said in my original post, I think it would be extremely silly to try such an experiment for real, for all sorts of reasons: Not properly trialled; probably cannot have a tryptophan-free diet without losing all sorts of other essential dietary needs; as @Trish points out, tryptophan needed elsewhere; etc, etc.
     
  14. daftasabrush

    daftasabrush Senior Member (Voting Rights)

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    The meaning is not the same as the "greater than" mathematical one, it's about forward and backward direction and which alleles are equivalent to others. If you check the orientation link on SNPedia above it explains positive and negative and how the letters are paired, eg:

    In terms of the nucleotides for that SNP, the pairing of A with T,and C with G, in the DNA double helix means that an A on the plus strand by definition is a T on the minus strand, and vice versa, and a C on the plus strand means a G on the minus strand (and vice versa).

    Each person's DNA analysis result will include the two alleles eg T > A.
     
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  15. daftasabrush

    daftasabrush Senior Member (Voting Rights)

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    Ron Davis has explicitly said: do not experiment with this. Doing so can put the body into a much worse state which it may not be possible to get out of.

    Tryptophan - Kynurenine is not the only tryptophan pathway, and there have already been huge safety concerns leading to L-typtophan supplements being withdrawn from use. Clearly we haven't developed the same condition as those taking L-typtophan so it is not simply a matter of lowering tryptophan. Tryptophan also impacts serotonin, and melatonin. Too much serotonin is also extremely dangerous (life threatening), yet too little is dangerous also.

    The point of my post was: how you can tell if you have one of those IDO2 gene mutations based on data analyzed from saliva?
    (But also, how to do comparisons in general - the ME/CFS Gene Study by Nancy Klimas has reported it's first results based on saliva sample consumer testing).
     
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  16. Barry

    Barry Senior Member (Voting Rights)

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    And the point for my post was to:
    • Make it very clear from the outset that to try anything for real would be very stupid.
    • Trying to understand something from a purely hypothetical, thought experiment perspective, which is a valid investigative approach.
     
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