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Poll: rs11627387 MTHFD1

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Kimsie, Feb 8, 2016.

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Do you have the rs11627387 mutation?

  1. I have the GG variant

    5 vote(s)
    62.5%
  2. I have the AG variant

    3 vote(s)
    37.5%
  3. I have the AA variant (risk)

    0 vote(s)
    0.0%
  1. Kimsie

    Kimsie Senior Member

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    rs12939757 (edit: this is supposed to say rs11627387) is a loss of function variant of MTHFD1 which is fairly common with AA (the risk allele) being about 12% on OpenSNP. I think this allele may be significant only when a person is experiencing oxidative stress.
     
    Last edited: Feb 8, 2016
  2. Valentijn

    Valentijn The Diabolic Logic

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    I think you've listed the wrong SNP here, since rs12939757 isn't on the MTHFD1 gene.

    What do you mean by "loss of function"? Why do you believe that rs11627387 is having a significant impact? What's the basis for suggesting that oxidative stress specifically interacts with this non-coding SNP?
     
  3. Kimsie

    Kimsie Senior Member

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    Yes, I had the wrong SNP in at first and I missed getting it changed in that one spot. It's supposed to be rs11627387. Sorry about that.
    This study found that it is associated with increased risk for heart defects (at least in hispanic women). I take this to be evidence that it is a loss of function change although perhaps that is slim evidence. I am planning to talk about my reasons for believing that it might be significant soon in another post to start a new thread because it is pretty complicated, but basically loss of function in MTHFD1 has been found to cause problems with thymidylate synthesis and methionine recycling (in a real person, not in a rat or mouse). Since MTHFD1 requires NADPH to go in the direction of 5,10-methyleneTHF, which is needed for thymidlylate and methionine synthesis, it seems logical to me that oxidative stress, which will drain NADPH, could increase the negative effects of loss of function mutations in MTHFD1. This SNP is only one of the possible SNP's involved. I would imagine that a person could have more than one SNP affecting the pathway, and that multiple SNP's would increase the effect.

    I am particularly interested in this SNP because my son with depression is AA for this SNP and I suspect that my son with schizophrenia is AA, too, because our 3rd son is AA, (our daughter is AG, and I am AG, but I suspect that my husband is AA.) I believe that my sons' problems are caused by loss of function SNP's in the MTHFD1 pathway, and this is the only one that I can find that they have homozygous mutations on, so far, for which I have evidence of loss of function. I am planning to explain about this in the other post when I can get it together.
     
    Philla likes this.
  4. Valentijn

    Valentijn The Diabolic Logic

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    That SNP has a very small effect size (slightly increased risk of cardiac birth defects), which would indicate the impact of it is relatively mild. It is extremely unlikely that it results in loss of gene function, especially since it has not been marked as pathogenic.
     
  5. Kimsie

    Kimsie Senior Member

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    Yes, by itself it wouldn't be significant, but in combination with other MTHFD1 mutations and with oxidative stress, it might add to the negative effect. Since it might only be significant in combination or with certain stress conditions, it would be less likely to be spotted as a loss of function mutation.

    If you happen to have a list of MTHFD1 loss of function mutations with their rs numbers, I would be interested in the information. It might be better to look at the combination of these mutations rather than one mutation. Maybe a poll of all of these mutations would be more informative.
     
  6. Kimsie

    Kimsie Senior Member

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    Also, why do you think that it does not result in any loss of function? What other reason could there be for it to have any impact on birth defects?
     
  7. mariovitali

    mariovitali Senior Member

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    @Kimsie

    MTHFD1 may be important for Choline absorption so i suggest you look into it.



    https://en.wikipedia.org/wiki/Choline
     
  8. Valentijn

    Valentijn The Diabolic Logic

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    I misunderstood what you meant by "loss of function". It can cover a huge range of impact, from making the gene completely nonfunctional to an insignificant down-regulation. I think I'd describe this one as being a mild down-regulation, for clarity.

    That the SNP only attains significance in a sub-sample is also a red flag. If the SNP in isolation has an impact in one human, it should have a similar impact in other humans. A couple things could be happening, other than actual significance solely in Hispanics. One possibility is that it's just a false positive, which happens a lot in SNP research of this type. Another possibility is that the SNP is in varying degrees of linkage disequilibrium in different ethnicities, and is merely reflecting the increased prevalence of the actually relevant SNP in one of those groups.

    I'd consider this study to provide weak evidence of a minor impact. It needs to be replicated to confirm any correlation, and it would be nice to see actual folate levels measured as well, which would provide much stronger and more direct evidence of a down-regulation.
     
  9. ahmo

    ahmo Senior Member

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    Northcoast NSW, Australia
    Lecithin + citicoline + Alpha GPC choline have helped my oxidative stress symptoms. Also, re choline:

     
    mariovitali likes this.
  10. Kimsie

    Kimsie Senior Member

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    Choline can be changed into betaine and recycle methionine through BHMT but taking a methionine supplement should help avoid draining choline, unless the person has a problem in the transsulferation pathway.
     
  11. Kimsie

    Kimsie Senior Member

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    I agree that the study is not very strong evidence, but it is some evidence that this SNP produces a mild down-regulation. But I disagree with your apparent assumption that a mild down-regulation is insignificant. I think for some people it can be the straw that breaks the camel's back when there are other "insignificant" factors added to it.
     
    PeterPositive, mariovitali and ahmo like this.
  12. aquariusgirl

    aquariusgirl Senior Member

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    GG here ....
     
  13. Kimsie

    Kimsie Senior Member

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    Here is another study where rs11627387 was found to be involved in the probability of birth defects, in this case TD defects. So far I haven't found any other studies with this SNP. In this study the risk was only increased when folate intake was low. I feel this is actually significant, because what I am looking for are SNP's that could cause the body to compensate by localizing MTHFD1 to the nucleus, at least under conditions of oxidative stress. I am not looking for SNP's that cause actual damage in and of themselves. It is the localization of MTHFD1 in the nucleus which causes undermethylation of the histones, according to my hypothesis, which I hope to post about soon.

    I have no way of knowing whether CFS/ME is affected by undermethylation or not. And this SNP is only one of several that could be involved it it was so. But if it is so, I do think it could be something affecting people who have problems with refeeding, since the thymidlyate pathway is involved.
     

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