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Glutathione-related polymorphisms in autism, and relation to ME/CFS

Discussion in 'Other Health News and Research' started by richvank, Apr 10, 2012.

  1. richvank

    richvank Senior Member

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    Hi, all.

    As many of you know, I have proposed the Glutathione DepletionMethylation Cycle Block (GD-MCB) hypothesis, which suggests that the onset of ME/CFS is caused by depletion of glutathione by some combination of a variety of physical, chemical, biological and/or psychological/emotional stressors, in a person who is genetically predisposed.

    Though there is considerable evidence from twin and family studies as well as individual polymorphism studies that a genetic predisposition exists, at least for the sporadic (non-cluster) cases, it has not been well-defined up to the present. I have suggested that it must consist of polymorphisms in genes that code for enzymes that are involved in the early part of the pathogenesis of ME/CFS. Otherwise, they would not be accessed, and would not have an impact on the likelihood of onset of ME/CFS.

    Based on these considerations, it would seem that the genetic predisposition toward developing ME/CFS must involve polymorphisms in genes coding for enzymes associated with glutathione. These have not yet been studied in ME/CFS.

    As many of you also know, I have argued that the basic biochemistry of ME/CFS is the same as that of autism. If this is true, one might expect that a similar genetic predisposition might be involved in autism.

    A recent paper reports on a study of glutathione-related polymorphisms in autism. Here is the abstract:

    J Neurodev Disord. 2011 Jun;3(2):132-43. Epub 2011 Mar 5.
    Glutathione pathway gene variation and risk of autism spectrum disorders.
    Bowers K, Li Q, Bressler J, Avramopoulos D, Newschaffer C, Fallin MD.
    Source
    Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St. room W6509, Baltimore, MD, 21205, USA.
    Abstract
    Despite evidence that autism is highly heritable with estimates of 15 or more genes involved, few studies have directly examined associations of multiple gene interactions. Since inability to effectively combat oxidative stress has been suggested as a mechanism of autism, we examined genetic variation 42 genes (308 single-nucleotide polymorphisms (SNPs)) related to glutathione, the most important antioxidant in the brain, for both marginal association and multi-gene interaction among 318 case-parent trios from The Autism Genetic Resource Exchange. Models of multi-SNP interactions were estimated using the trio Logic Regression method. A three-SNP joint effect was observed for genotype combinations of SNPs in glutaredoxin, glutaredoxin 3 (GLRX3), and cystathione gamma lyase (CTH); OR=3.78, 95% CI: 2.36, 6.04. Marginal associations were observed for four genes including two involved in the three-way interaction: CTH, alcohol dehydrogenase 5, gamma-glutamylcysteine synthetase, catalytic subunit and GLRX3. These results suggest that variation in genes involved in counterbalancing oxidative stress may contribute to autism, though replication is necessary.
    PMID: 21484198


    As the abstract reports, the study found that a combination of polymorphisms in three genes associated with glutathione predicts having almost a fourfold higher risk of developing autism. They were the genes that code for the enzymes glutaredoxin, glutaredoxin 3 and cystathionine gamma lyase (also called cystathionase). The study also found that a combination of polymorphisms in four genes related to glutathione had a marginal association with greater risk of developing autism.

    Note that cystathionine gamma lyase is the second enzyme in the transsulfuration pathway. One of its reaction products is cysteine, which is usually the rate-limiting amino acid for the synthesis of glutathione. A polymorphism in this enzyme would thus impact the ability to synthesize glutathione.

    The glutaredoxins are small proteins that catalyze glutathione-dependent disulfide oxidoreduction reactions in a coupled system with NADPH, GSH, and glutathione reductase. They use glutathione to reduce low molecular weight disulfides and proteins. Polymorphisms in these enzymes may impact the demand for glutathione or the ability to recycle glutathione when it becomes oxidized.

    Two additional genes that were involve in a marginal association with the risk of developing autism were the genes that code for alcohol dehydrogenase 5 and gamma- glutamylcysteine synthetase.

    The former is also known as formaldehyde dehydrogenase. It oxidizes formaldehyde-glutathione conjugates, releasing glutathione to be used again. A polymorphism in this gene may therefore cause glutathione to be sequestered as this conjugate, making less of it available for other purposes.

    Gamma-glutamylsynthetase (also called glutamate cysteine lygase) is the rate-limiting enzyme for the synthesis of glutathione. A polymorphism in this enzyme would affect the ability to synthesize glutathione.

    I suggest that if a similar study were done in ME/CFS, similar results would be found. While this would not directly affect treatment of ME/CFS, I think it would draw more research and clinical attention to this proposed causal mechanism, and in the long run, I think that would improve treatment.

    Best regards,

    Rich
    Merry and fla like this.
  2. globalpilot

    globalpilot Senior Member

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    Hi Rich,
    Do you know which genes these are on the 23andme ?

    Susan
  3. anne_likes_red

    anne_likes_red Senior Member

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    Thanks for the explanation about which genes (and what they do exactly) Rich.
    Very interesting.
    Who would be open to doing a similar study for us I wonder?

    Anne.
  4. richvank

    richvank Senior Member

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    Hi, Susan.

    Yes, I do. By using the rs numbers, I was able to find all but one of the SNPs mentioned in the paper, but several of them were assigned to "intergenic" rather than to the genes they were assigned to in the paper, and the CTH SNP was assigned to a gene called ANKRD13C. I don't know what to make of that. Anyway, here are the genes and the SNPs that were assigned to them in the paper, as well as my own data for the SNPs from 23andme. I've included some additional ones that were mentioned in the paper as having a suggestive association, even though they are not the main ones that were found to be associated. As you know, I don't have ME/CFS.

    Glutaredoxin GLRX rs11135434 CT
    Glutaredoxin-3 GLRX3 rs3750834 AA and rs11017128 AA
    Cystathionine gamma lyase CTH rs12737233 TT
    Alcohol dehydrogenase-5 ADH5 rs1230155 AA and rs1154415 CC
    Gamma-glutamylcysteine synthetase GCLC rs524553 TT and rs761141 TT
    Glutathione S-transferase A2 GSTA2 rs2608615 CC
    Glutathione Peroxidase-4 GPX4 rs10439143 no call

    Best regards,

    Rich
  5. adreno

    adreno 3% neanderthal

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    Tundras of Europa
    Well, in that case, couldn't we make our own informal study here, if people post their results?
  6. richvank

    richvank Senior Member

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    Hi, adreno.

    We could try that. Please see my post #4 above. But note that in the paper they did a fairly sophisticated statistical analysis in which they considered three SNPs together. When they did this, they found significance that did not show up when the SNPs were looked at individually. It seems to be combinations of SNPs that are important, not just single ones.

    Best regards,

    Rich
  7. globalpilot

    globalpilot Senior Member

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    Hi Rich,
    I put my results besides yours. I don't think there is a genetic issue with these genes in my case.
    Isn't it nice to be able to go teh database and pull these results ?

    GP

  8. Valentijn

    Valentijn Activity Level: 3

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    Is it possible to get tested for actual levels of those enzymes instead of relying upon genetic testing? And is there a way to treat specific enzyme deficiencies?
  9. hixxy

    hixxy Woof woof

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    I'm just looking for a little bit of a lesson on interpreting this kind of stuff. The distribution for this SNP from dbSNP is as follows:

    European - Genotypes: 0.018(CC) 0.221(CT) 0.761(TT) - Alleles: 0.128(C) 0.872(T)

    If what rich put earlier on is supposed to be considered risk 'TT'. Doesn't this contradict that the common allele is protective, therefore the minor is the risk allele, ie. 'CC'.

    Or going by genotypes in order of highest risk to lowest: CC, CT, TT

    OR have I got it all wrong? I'd like to look at it further and try figure out the combinations of mutations. If the first one isn't right tho, there's no point continuing with the rest.
  10. hixxy

    hixxy Woof woof

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    Also, doesn't this just fly in the face of Amy Yasko's selection of SNPs?
  11. nanonug

    nanonug Senior Member

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    Surprise, surprise! :D
  12. nanonug

    nanonug Senior Member

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    Rich doesn't have ME. He's TT. By the way, I am TT too.
  13. richvank

    richvank Senior Member

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    Hi, Hixxy.

    No, I don't think you have it all wrong. The most common genotype in the European population for this polymorphism is TT, and for this polymorphism, that's the protective one. You may be referring to what I posted earlier about the PON1 polymorphism. In that case T was the genotype with the higher risk. Which one is protective vs. which one poses the risk depends on which polymorphism we are talking about.
  14. richvank

    richvank Senior Member

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    Hi, hixxy.

    I think that the selection of SNPs depends on the purpose of the selection. In this thread, I am interested in which SNPs influence the likelihood of developing ME/CFS (or autism, in the case of the study I cited). Amy says she has selected SNPs on the basis of which ones affect how she suggests treating these conditions. I think those will be different sets of SNPs.

    Best regards,

    Rich
  15. hixxy

    hixxy Woof woof

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    Ah, I misunderstood. I didn't realise you were posting your results -- I thought you were posting indicators of risk. My bad.
  16. hixxy

    hixxy Woof woof

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    I too am TT.
  17. hixxy

    hixxy Woof woof

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    Using the SNP interraction table shouldn't you be able to do a study based on CFS patients 23andMe results?

    It seems the bulk of the work has been done. The table isn't that straight forward to understand, but taken in context of the rest of the information included in the study it doesn't seem too difficult to work with.
  18. roxie60

    roxie60 Senior Member

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    In what way Hixxy, in the genes she is testing or her conclusions about the genes? I am strongly considering the 23andme test and was considering Amy's (I'm leaning towards 23andme for costs becuase I also want to get the methylation pathways paenl if my Dr will ever call me back).
  19. roxie60

    roxie60 Senior Member

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    So if the genes test comes back as TT that means one does not have ME/CFS?

    Would methylation pathway issues or gut issues then manifest similar symptoms as ME/CFS if ones genes are TT? Still very sick but not ME/CFS?
  20. nanonug

    nanonug Senior Member

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    Unfortunately, no!

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