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SNPs for GTP Cyclohydrolase I (GCH1), rate-limiting enzyme for BH4 - relation to NOS

Discussion in 'Genetic Testing and SNPs' started by nandixon, Sep 26, 2012.

  1. jepps

    jepps Senior Member

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    Many thanks nandison.

    rs10483639 GG, rs3783641 TT, rs8007267 CC are my results, this means, I can build up BH4. But I have MTHFR A1298C, COMT H62H+V158M, VDT Taq, and CBS C699T, all of this heterozygot, and I have histamins, aluminium and bacterials to detoxify, so my BH4 will be depleted, an I will take BH4 2,5 mg/day.

    I wonder, if there is any link, where I can find the risk alleles by myself?
     
  2. Valentijn

    Valentijn Activity Level: 3

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    Here's a spreadsheet showing rare genotypes for 11 ME/CFS patients and 11 controls. Purple = less than 1% prevalence in the general population, red = 1 - 2.5%, and yellow = 5 - 10% (if there was orange, it would indicate 2.5 - 5%). SNPs where all patients and controls have the same genotype, or no genotype is uncommon (less than 10%) have been excluded, as well as duplicate SNPs where everyone always has the same genotype across those SNPs.

    GCH1.gif

    So basically we have identical results compared to the controls, aside from one outlier, P6 (me). Though the other rare results (and even non-rare results) could of course be having an impact. I've also seen results from another patient here, who was heterozygous for a rare missense mutation on GCH1 at rs41298432 (rare allele A).

    On a personal note, I also have a homozygous MTRR issue resulting in the efficacy of that gene being reduced by a factor of 3.5. How would a potentially slow GCH1 interact with that definitely slow MTRR?
     
  3. nandixon

    nandixon Senior Member

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    Which SNP(s) in MTRR are you referring to?

    Off hand, I can't think of a perfectly direct interaction between reduced amounts of BH4 and reduced MTRR function. Indirectly, lower amounts of BH4 could promote nitric oxide synthase (NOS) decoupling, which reduces antioxidant status, and thus may make it more likely for cobalamin to become oxidized while MTR is using it for methylation of homocysteine. In other words, it may place a greater burden on MTRR's ability to recycle oxidized cobalamin for use by MTR. Just a guess, though. There may be more direct effects.
     
  4. Valentijn

    Valentijn Activity Level: 3

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    MTRR A66G. Thanks for the extra info - someone mentioned a connection earlier, but I wasn't sure what that connection would be :p
     
  5. Beatnik

    Beatnik

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    MTRR 66 transfers mb12 to MS to generate Metionine. So, if MS is slow, 5mthf+ HCY is slow, and this reaction generates BH2 (then hidroxylated back to bh4 by dhpr) in the direct process and in the reverse process. when 5mthf (ch3) is back to methylene THF (CH2) generates BH4 itself.(1298)

    See if you have MTHFD or MTHFS cause this mutations are critical for BH4 also, not only 677/1298. In order to generate 5mthf you need first generate formyl, and then methenyl, and then methylene THF.

    MTHFR is only responsible for the last step (Ch2 to Ch3 thf (677) and back to ch2 thf(1298)). Not easy, but understandable.

    So i´m against Yasko at this point, 677 mthfd, mthfs are also important for BH4 as far as you can see in the diagram showed. Direct mthfr reaction generates BH2 and inverse reactions generates bh4, but both are important. Dhpr is also important and off course CBS. The whole folate and Methionine cycle are also important, if they are slowed at one point , bh4 is depleted.

    Another key point forgotten by Yasko is Mitochondrial Superoxide Generation, that also limits BH4 but i have no time to explain everything.

    Regards.


    [​IMG]
    [​IMG]
     
    Last edited: Feb 9, 2014
    roxie60 and helen1 like this.
  6. trollo

    trollo Senior Member

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    Please explain, wich one is the Polymorphism and wich the wild type?? The one into brackets?
     
  7. trollo

    trollo Senior Member

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    Also Valentjin... what do those C# nd P# mean?
     
  8. Valentijn

    Valentijn Activity Level: 3

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    C = Control, P = Patient.
     
  9. trollo

    trollo Senior Member

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    Does the rarity necesarily means 'bad'???
     
  10. Valentijn

    Valentijn Activity Level: 3

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    Certainly not.
     
  11. trollo

    trollo Senior Member

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    so basically having one purple or red means nothing?
     
  12. trollo

    trollo Senior Member

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    Somebody knows where is it possible to know all SNPs for GCH1 and TH genes which are related to reduced dopamine??
     
  13. Valentijn

    Valentijn Activity Level: 3

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    No, it means that they have rare SNPs on the gene.

    This might potentially be of interest, for example if many ME/CFS patients have a lot of rare SNPs on the same gene.
     
  14. trollo

    trollo Senior Member

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    ok but there are GCH1 and TH snps that are known to be cause of dopamine defciency, i m interested on them only. Where are them?
     
  15. mariovitali

    mariovitali Senior Member

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  16. nandixon

    nandixon Senior Member

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    Mario, if you are GG for rs2016546 in GCHFR, then you have the normal (-/-) result for that SNP.
     
  17. mariovitali

    mariovitali Senior Member

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    Ah yes, Thanks!

    I have the following results in my 23andme data regarding GCH1 :

    rs12147422 - TT
    rs3783637 - CC
    rs3783641 - AT
    rs41298442 - TT
    rs4411417 - CT
    rs752688 - CT
    rs841 - AG
    rs998259 - CC
    rs7147286 - AG

    Do you think i should supplement with BH4?
     
    Last edited: May 4, 2015
  18. nandixon

    nandixon Senior Member

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    @mariovitali

    There are two additional SNPs for GCH1, rs10483639 and rs8007267, which 23andMe refers to as "intergenic" and which are actually located in the 3'-UTR and 5'-UTR/promoter regions, respectively, of GCH1.

    Can you tell me what your results are for those two SNPs?
     
  19. mariovitali

    mariovitali Senior Member

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    Sure,this is what it looks like :

    rs10483639 : CG
    rs8007267 : CT
     
  20. nandixon

    nandixon Senior Member

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    @mariovitali

    Of the relatively common SNPs in GCHI, like those we're looking at here, the most well-studied and most significant (for European ethnicities) seem to be rs841, and a haplotype of three SNPs comprised of:

    rs10483639
    rs3783641
    rs8007267

    That 3-SNP haplotype is referred to by SNPedia/Promethease as "gs224." The risk alleles for each of the three SNPs above are C, A and T, respectively. (The risk allele for rs841 is A.)

    Rs841, in European ethnicities, is in strong "linkage disequilibrium" with gs224 (see the reference in this post). This means that, typically, the overall genotype (homozygous or heterozygous) a person has for gs224 should match pretty well with the result for rs841. (Note that 23andMe no longer tests for rs841 with their latest test, which is why I'm mentioning this for other people.)

    So, for example, you're heterozygous for both rs841 and for gs224. (For other people, it often won't necessarily happen that all 3 SNPs within gs224 each perfectly matches the genotype for rs841; e.g., see this post.)

    I think rs841 is probably the actual, functional, detrimental SNP (affecting gene expression), but it may be gs224 as a whole, instead, that is the problem - or both, or neither (it's still not perfectly clear, I don't think). In any event, gs224 can be used as a good substitute for rs841, and vice versa, for people of European ethnicity.

    GCH1 is the rate-limiting step for the production of BH4, and rs841 (or gs224) appears to affect how much BH4 is made. That SNP (or haplotype) may be detrimental, especially in diseases involving oxidative stress. At a minimum, it probably exacerbates oxidative stress (by promoting uncoupling of the nitric oxide synthases to produce superoxide and peroxynitrite), but it might also possibly contribute to the development of disease in the first place (by working in conjunction with other "bad" SNPs and/or epigenetic factors, including diet driven) or to perpetuate a disease. Or, in the words of the authors of the reference given above (at p.198 of the article):


    It wouldn't be possible to tell for certain whether a person might actually have a problem with reduced BH4 production from the results of rs841/gs224 alone, I don't think. And in your case, being heterozygous makes that less likely than being homozygous. But it may be worth exploring to see if something might help.

    I don't have enough energy to go into too much more detail, but obvious categories of things to try are (there's some overlap):

    1. Increase GCH1 expression
    2. Prevent inhibition of GCH1 expression
    3. Decrease loss (degradation) of the enzyme (GTPCH1)
    4. Decrease loss (oxidation) of BH4
    5. Increase BH4

    I think losartan might hold some promise to increase BH4 based on this study (and others not directly related to BH4):

    Angiotensin II type 1 receptor blocker ameliorates uncoupled endothelial nitric oxide synthase in rats with experimental diabetic nephropathy

    In theory, direct BH4 supplementation would seem to have some significant potential problems, but @Mimi has apparently had some success in that regard. (I'm curious if it's still working for her?)

    The problem is that it turns out that the ratio of BH4 to its oxidized form, BH2, is just as important as the absolute amount of BH4, in terms of keeping NOS coupled. And keeping a high BH4:BH2 ratio while supplementing BH4 would seem very tricky given how much oxidative stress is present in ME/CFS. There may be a "Goldilocks" amount, though, that can work. Or alternatively, supplementing a very large amount of BH4 so that it can act as its own "built-in" antioxidant might be possible - except for cost.

    A couple of years ago, I tried the "homeopathic" 2.5mg BH4 capsules that are available. I seemingly had a positive response to the very first capsule, but then nothing after that, even trying up to as much as ten capsules at once. Perhaps I was running into the BH4:BH2 ratio problem, and needed to try either less than 2.5mg (seems a bit unlikely), or a lot more than 25mg.

    On the other hand, BH4 is extremely easily oxidized when not in the stabilized (patented) Kuvan tablet form. And I'm suspicious that some of the suppliers are simply crushing the tablets to make smaller doses, and they may not be taking great enough care to protect against oxygen. So I might give direct supplementation another try with the actual Kuvan tablets at some point.

    As far as trying to prevent loss of BH4 already present, that's going to be partly about decreasing overall oxidative stress, e.g., with antioxidants. Methylfolate in theory should be especially helpful, but too much might contribute to hypermethylation of the promoter region of GCH1 and shut down its expression, especially when used with large amounts of vitamin B12.
     
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