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Fighting Stress with Adenosine Antagonists.

Discussion in 'Other Health News and Research' started by Ema, Jan 6, 2014.

  1. Ema

    Ema Senior Member

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    And go figure, thanks to @Valentijn, I now know that I have a very rare mutation of these receptors! I wish there was more research on them...

    continued at http://blogs.scientificamerican.com...0/fighting-stress-with-adenosine-antagonists/
     
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  2. Valentijn

    Valentijn Senior Member

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    Here's a nice excel spreedsheet of the ADORA receptor SNPs, in 11 ME/CFS patients and 11 controls. Red boxes indicate a genotype present in 1 - 2.5% of the general population, orange is 2.5 - 5%, and yellow in 5 - 10%. SNPs for which there is no variation, or for which all variations are common, or which are duplicates of other SNPs have been excluded.

    ADORA.gif

    There's not much difference for patients versus controls in ADORA2A, ADORA2B, or ADORA3. However there's a pretty striking difference for ADORA1. On that gene, ME/CFS patients have 5 SNPs in the 2.5 - 5% (orange) prevalence range versus 0 for the controls, and ME/CFS patients have 7 SNPs in the 5 - 10% (yellow) range versus 1 for the controls.
     
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  3. Aileen

    Aileen Senior Member

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    @Valentijn I wasn't able to get your rare allele program to work on my computer but I did give you some SNPs. Is my data included in the above table or do you need me to give it to you?
     
  4. Ema

    Ema Senior Member

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    Wasn't my rare mutation in another protein that impacted ADORA2A though and not in the ADORA2A itself?
     
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  5. Valentijn

    Valentijn Senior Member

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    It looks like I just have a small set from you, probably for a single gene. If you're willing to send me your entire 23andMe file, I can add it to our ME/CFS patient spreadsheet. I'll contact you with info on how to do it. It also looks like you had the Mac issues with the rare gene analysis program, so I can run that for you while I'm at it.
     
  6. Valentijn

    Valentijn Senior Member

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    Yours was rs17595410 on USP4. USP4 deubiquinates ADORA2A, which increases the amount of functional ADORA2A receptor on the cell surface. So a problem with USP4 might result in a reduction of ADORA2A receptors.
     
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  7. Valentijn

    Valentijn Senior Member

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    Here's a bigger and messier Excel spreadsheet of the ADCY1 - ADCY10 genes, which create the adenylate cyclases. I'm not really sure what it does, except that it messes with adenosine somehow :nerd:

    ADCY_full.gif

    Basically the rare SNPs are weighted based on how rare they are, and then totaled to see if we're more or less rare than the controls. Overall we're about twice as rare, with the biggest differences seen in ADCY3 and ADCY5, where we're about 5 times as rare :alien: ADCY2, ADCY6, and ADCY8 showed little or no difference.

    There were only a couple known missense mutations, and little research regarding up- or down-regulation, though ADCY5 contains a few rare SNPs in the ME/CFS patients which are known to be protective against developing diabetes and a higher birthweight. It's possible that the SNPs which are beneficial in one context are a vulnerability in another context.
     
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  8. Ema

    Ema Senior Member

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    So where do we find out more about ADCY8?
     
  9. beaverfury

    beaverfury beaverfury

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    Can someone make me a coffee?

    I'd ADORA1
     
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  10. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    Ema have u tried modafinil. I have been getting good effects using very low doses like 25mg. Normal dose is 100 to 200mg. I find it improves cognitive energy but not buzzing around over stimulated. I thought its main action was working with dopamine and noradrenaline but have read it works on adenosine as well as the above.
     
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  11. Ema

    Ema Senior Member

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    I haven't tried it. Sounds like I should look into it. Thanks!
     
  12. Valentijn

    Valentijn Senior Member

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  13. Valentijn

    Valentijn Senior Member

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    Here's a few more adenosine-related genes, ADCYAP1, ADA, and ADK:

    ADCYAP1-ADA.gif


    ADK.gif

    So pretty normal for ADCYAP1 and ADA (much more so than the controls), but ADK is looking a bit wonky for several of us. ADK is adenosine kinase, which converts adenosine into AMP and ADP.
     
  14. Ema

    Ema Senior Member

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    For the first time, the controls and the patients look reversed in the ADA table.

    Do you have anything for AMPD1?
     
  15. Valentijn

    Valentijn Senior Member

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    One possibility is that some SNPs are protective, or at least advantageous in certain situations. But that could just as easily apply to our own rare SNPs :p

    Somehow I missed AMPD1, though I have a big list I'm going through:
    ADSS
    ADSSL1
    ADSL

    AK1
    AHCY
    APRT
    AMPD1

    GUK1
    UBC
    USP4

    PRPS1
    PPAT
    PFAS

    GART (E1, E2, E3)
    PAICS (E1, E2)
    ADSLATIC (E1, E2)

    IMPDH1
    IMPDH2

    GMP synthase
    GMPR
    GMPR2

    PNP - Purine_nucleoside_phosphorylase
    XDH
    HPRT1

    Anything else involving adenosine I might be missing?
     
  16. Valentijn

    Valentijn Senior Member

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    Here's ADSS, ADSSL1, AMPD1, AMPD2, and AMPD3. ADSL didn't have any interesting SNPs for us or the controls.

    ADSS-AMPD.gif

    So not much going on with ADSS, ADSSL1, or AMPD2.

    But AMPD1 is quite interesting - rs17602729, which is heterozygous in 4 patients and 0 controls, is a known pathogenic missense mutation. When homozygous or compound heterozygous, it causes muscle pain and weakness due to myoadenylate deaminase deficiency, starting in early childhood. http://omim.org/entry/102770#0001 has some more data. It's possible that being heterozygous is causing a milder and/or later-onset version, or has created a vulnerability which some other factor (such as an infection or immune reaction) has exploited or exacerbated.

    AMPD3 is also somewhat interesting. Mutations can result in an absence of adenylate deaminase in blood cells, but it isn't known to cause any illness thus far. But again, it might be interacting with an external factor to cause problems. Even heterozygous mutations in that gene can result in reduced adenylate deaminase levels.
     
  17. Ema

    Ema Senior Member

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    Yes, yes, yes! That's my theory too an AMPD1...it is slow and thus adenosine builds up and eventually induces hibernation syndrome and then takes out the immune system as well.

    Adenosine is antiinflammatory except in excess when it seems to do the opposite.

    I know not everyone had high adenosine on the methylation panel but it was common enough that RichvanK took note. And people have been studying the problems in purine metabolism for ages in ME/CFS.

    Great work on all this, @Valentijn. It's very interesting to see it all laid out in color like this.
     
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  18. Valentijn

    Valentijn Senior Member

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    Here's AK1 - AK5 and CMPK1 and CMPK2. Nothing too interesting, compared to the controls.

    AK-CMPK.gif

    AK is adenylate kinase, which converts ADP from and into ATP + AMP. CMPK participates in converting ATP into ADP.
     
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  19. alex3619

    alex3619 Senior Member

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    This is very often the case. The classic case is sickle cell anemia, which can confer immunity to malaria, but its also the case with detox genes. Some people in the population are always more vulnerable to some chemicals, and others more resistant. Its a genetic advantage to the population, though not always to the individual.
     
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  20. wastwater

    wastwater Senior Member

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    On Malacards gene site I saw a mention of RGS2 that acts on PRKG1 and ADCY5 in relation to my rare genetic disorder.And this http://www.uniprot.org/uniprot/P41220
    RGS2 links to anxiety Alzheimer's brucellosis T cell activation B cells and IL-2
     
    Last edited: Feb 5, 2017

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