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Ion Channel SNP Paper

Discussion in 'General ME/CFS News' started by Jonathan Edwards, May 11, 2015.

  1. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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  2. Gijs

    Gijs Senior Member

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  3. A.B.

    A.B. Senior Member

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    In my case there is definitely some problem with glucose utilization, blood sugar regulation, or something in that area.

    What other functions does this channel have?

    Does magnesium have anything to do with TRPM3 function? Because magnesium seems to often be somewhat helpful.
     
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  4. Marco

    Marco Grrrrrrr!

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    Interesting discussion (with the stats caveat of course).

    Probably nothing, but TRPM3 channels are inhibited by progesterone (with anecdotal reports of ME/CFS remission during pregnancy) :

    http://www.ncbi.nlm.nih.gov/pubmed/22000496/
     
  5. adreno

    adreno PR activist

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    From the paper:

     
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  6. adreno

    adreno PR activist

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    Hm. Progesterone is a metabolite of pregnenolone.
     
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  7. Simon

    Simon

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    Unfortunately the paper gives very little detail on the statistical analysis used, and they don't explicityly state they have corrected for multiple comparisons (eg by some kind of False Discovery Rate correction, FDR).
    If they haven't used FDR it would throw into doubt the findings, since with 233 SNPs analysed there would be expected to be 12 false positives, compared with 13 positives found in this study. The p values were hardly stunning, with only 3 SNPs making it below 0.01 (best was for TRMP3, 44% in patients v 29% in controls, p=0.003).

    That said, the study used the open-source PLINK: Whole genome data analysis toolset developed by researchers at Harvard and MIT amongst others, and this may have multiple comparison corrections built into it. I will try to find out what the authors did re multiple comparison corrections.
     
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  8. adreno

    adreno PR activist

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    Nothing gets past you, @Simon.
     
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  9. taniaaust1

    taniaaust1 Senior Member

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    I don't know if its the TRPM channels or not but in my 23andme raw data when I was looking at my double copy mutations in the past, I found I had double copy gene mutations in the ion channels to do with calcium. It was one of the things which had interested me in my results which I wondered how it was affecting me. I found those mutations when my raw data was put through through Valenjtns program picking out the more uncommon gene mutations.

    I'll have to take another look at exactly what those mutations were so others can check these ion channel ones out too.
     
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  10. Marco

    Marco Grrrrrrr!

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    That's what I'd assumed but possibly not a safe assumption to make.

    ETA - The software offers corrections for multiple comparisons such as Bonferroni but like anything else I guess you have to understand the data, software and the most appropriate analysis.
     
    Last edited: May 11, 2015
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  11. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    Maybe that's why I started the thread!
     
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  12. taniaaust1

    taniaaust1 Senior Member

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    This info may interesting to someone
    http://www2.montana.edu/cftr/ionchannelprimers/beginners4.htm (has a lot more supposedly "beginners" info explaining different ion channels)

    Has anyone else noticed a lot of mutations around calcium or the calcium ion channel in their results compared to the other stuff if you are analysing all the more uncommon mutations? I have many calcium ones showing up among my results, its one of the most common types of mutations seen in my test results. (I still got a lot of my more uncommon mutations to analyse)

    I have homozygous mutations in the following areas

    ABC B4 I have lots of mutations in it (affects ATP)
    rs6977539 CC,
    rs6957680 GG,
    rs6956661 AA,
    rs11768699 TT,
    rs10487804 AA ,
    rs17149547 GG
    LONP1 (mitochrondria, ATP) rs11085147 TT
    CROT (transport of Acyl-CoA which converts to ATP) rs7786781 CC

    CACNA1S - Calicum channel rs12239772 GG
    RIMS1 - regulates calcium channels and insulin rs9442770 AA
    RYR3 - encodes a receptor to release calcium rs16971754 CC
    SSR1 - binds calcium to the cell ER membrane rs11243152 AA

    SCN2B (sodium channel activity in muscle cell action protential and sodium channel regulation) rs11216799 AA
    SLC9A2 (several of these) Its involved in PH regulation and plays important role in colonic sodium absorption rs11674245 AA, rs1016160 AA

    SLC4A4 (has pathways for all kinds of things, metal ions, regulates bicarb secretion, intercellular PH, glucose) rs13147721 AA

    HOMER2 This family regulates glutamate receptors rs7170046 TT
     
    Last edited: May 11, 2015
  13. Simon

    Simon

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    Thanks :)

    Good news: just waiting for final confirmation from Prof Sonya Marshall-Gradisnik, but it appears the authors DID correct for multiple comparisons - and there are more papers to come on this work. Which means we can all get on with discussing this paper's findings.
     
    Last edited: May 11, 2015
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  14. Snow Leopard

    Snow Leopard Hibernating

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    The finding is interesting, but with caveats - ME/CFS is not a purely genetic disorder, or patients would have it from birth. So at most, this suggests increased susceptibility to inducing some as yet unknown immunological loop. Is it a clue perhaps, or a red herring?

    Speaking of which, and this is a good thread as any to mention this, @Jonathan Edwards, what do you think about the following paper (and the hypothesis that the SNP leads to increased risk of autoimmune illness?)

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982386/
     
  15. sue la-la

    sue la-la

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    There's a new template in LiveWello, for the 13 significant SNP from this study.
    Sadly, the most recent 23andMe bead chip (?) only reports a few of them.
     
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  16. Gondwanaland

    Gondwanaland Senior Member

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    Can someone please rephrase this paragraph for the cognitively impaired?
     
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  17. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    The Fc-gamma-RIIc paper is just what I would have expected on the basis of our model of autoimmunity. If there is a functional polymorphism it ought to affect autoimmunity rates - probably in a fairly broad fashion.

    I have not yet worked out in my mind how a genetic ion channel variant would be likely to predispose to ME if based on an immune loop. It might alter B cell thresholds, again in a broad fashion, but why would it then only be linked to ME (and maybe migraine?). If the ion channel was acting as antigen then it would perhaps be odd for several SNPs to turn up. One could build a model but it seems awkward to me. What seems maybe more likely is that an ion channel variant could predispose to a neural loop - that might be set of either immunologically or otherwise. That makes more sense to me but it suggests that the ion channel might not have any direct relevance to immunology here.
     
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  18. Marco

    Marco Grrrrrrr!

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    I agree that it's unlikely that this is a direct cause of ME/CFS - more likely that it may contribute risk for developing a range of conditions involving nociception. I don't agree necessarily though that 'patients would have it from birth'. Whatever the mechanism I could imagine SNPs like this might predispose one to nociceptive 'wind up' (or long term potentiation) that might then trigger a self-perpetuating loop. You do not have 'it' from birth but you may have a risk factor that interacts with environmental stressors/stochastic mechanisms.
     
    Last edited: May 11, 2015
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  19. Gijs

    Gijs Senior Member

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    I don't believe ME is primarly an immuneproblem.
     
  20. Snow Leopard

    Snow Leopard Hibernating

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