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BH4 - GCH1 Question

Discussion in 'Genetic Testing and SNPs' started by Mimi, Jan 24, 2015.

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Do you have a GCH1 mutation?

  1. Yes

    19 vote(s)
    79.2%
  2. No

    5 vote(s)
    20.8%
  1. Mimi

    Mimi Senior Member

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    Medford, OR
    GCH1 encodes GTPCH1, the rate-limiting enzyme for BH4 synthesis. I'm curious to find out if anyone else has a mutation to this gene because low BH4 appears like it might explain a lot of the pathophysiology of ME/CFS. If so, it could lead to new treatments. To find out if you have a GCH1 SNP, check your 23andme raw data or run it through Promethease.
     
    Last edited: Jan 24, 2015
    Hutan likes this.
  2. ahmo

    ahmo Senior Member

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    BH4 is a key player in Martin Pall's theory about the nitric oxide cycle and how it affects those of us with ME, MCS, and a host of other illnesses. His website and a long video are linked below. The vid includes many slides After the initial presentation he goes into the specifice illnesses. The last 20" are his suggestions for countering the effects. I've tried to understand his work over the years, it's slowly beginning to sink in. I found the vid very helpful.

    http://www.thetenthparadigm.org/cfsweb.htm

    https://www.youtube.com/watch?x-yt-...r_detailpage&x-yt-ts=1421914688&v=6A7r1gemjto
     
  3. Mimi

    Mimi Senior Member

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    Thanks, ahmo. I will watch it. I have read his protocols and found that while he did everything to try and raise BH4 levels, he did not attempt direct supplementation. I actually wrote to him and asked about it but he never responded. Later I learned that there were some earlier misconceptions about BH4 and NO - that high levels of NO could be dangerous and therefore so could direct supplementation with BH4. That myth was abolished when researchers realized that high levels of peroxynitrite were the problem. Higher BH4 actually means lower ONOO-. But AFAIK, M. Pall did not update his protocol.
     
    Last edited: Jan 24, 2015
  4. Valentijn

    Valentijn The Diabolic Logic

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    How are you determining what constitutes a "mutation"? Which alleles of which SNPs are supposed to have a negative impact?
     
  5. nandixon

    nandixon Senior Member

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    I think she's thinking that a "SNP" is inherently a bad thing...

    Everyone who tested with 23andMe will have 38 SNPs listed (at least at the time the v3 chip was being used).

    I don't have enough energy to explain to her how the whole thing works.
     
  6. Mimi

    Mimi Senior Member

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    Medford, OR
    I don't know if GCH1 SNPs are fully understood. I'm sure I don't understand them. But even if GCH1 turns out to be totally irrelevant to our illness, BH4 may still be helpful. It is very evident in my case and in other people I know who have tried it. It also can aggravate, so like any powerful substance, it needs to be approached with caution.
     
    Last edited: Jan 24, 2015
  7. Mimi

    Mimi Senior Member

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    Hi Valentijn, I've deleted that part of my post so as not to confuse people by my own lack of understanding.
     
  8. Gondwanaland

    Gondwanaland Senior Member

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    I am confused about what to look for. From my (and my husband's) 23andMe raw data I can list our +/-, since we are the same +/+ (or -/-) for all the other SNPs:

    myself
    DH

    AG rs10131232 A or G
    GG

    GT rs2878169 G or T
    GG

    GG rs7492600 G or T
    GT

    TT rs12147422 C or T
    CT

    CC rs3783637 C or T
    CT

    CC rs11158026 C or T
    CT

    CT rs998259 C or T
    CT

    GG rs7147286 A or G
    AG

    CT rs3783642 C or T
    CT

    I found my Promethease report just confusing :confused:
    Edit to add: my 23and Me version is the one from November 2014 with less SNPs tested
     
    Last edited: Jan 25, 2015
  9. ukxmrv

    ukxmrv Senior Member

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    London
    rs10131232 AG

    rs2878169 GT

    rs7492600 GG

    rs12147422 TT

    rs3783637 CC

    rs11158026 can't find

    rs998259 CT

    rs7147286 GG

    rs3783642 CT
     
  10. Gondwanaland

    Gondwanaland Senior Member

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    @ukxmrv how did you know those homozigous you listed are +/+ and not -/-? Or are you just posting the same ones I posted?
     
  11. ukxmrv

    ukxmrv Senior Member

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    I took mine from 23andme raw data and just for the SNP's you listed. Sorry brain is totally fried now so will have to come back and look at this again. Probably best if I leave it for now as will only confuse things.
    Apologies for that.
     
  12. nandixon

    nandixon Senior Member

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    Here are the major and minor alleles (Major> Minor) for the SNPs given by 23andMe with my results as well.

    The GCH1 gene contains a large number of blocks of haplotypes, so it may appear you have lots of heterozygous (+/-) or homozygous (+/+) results when in reality you may have just a few because many of the SNPs are closely linked in groups that are inherited together.

    (With just a cursory look, I think rs41298442 might be the only true mutation 23andMe provides, i.e., one that definitively causes disease. It's highly unlikely you would have this one and not know about it already.)

    To research any SNPs of interest you can replace the rs# in the links below with any one you like:

    PubMed: http://www.ncbi.nlm.nih.gov/pubmed/?term=rs841

    Snpedia: http://www.snpedia.com/index.php/Rs841

    dbSNP: http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=841

    OpenSNP: https://opensnp.org/snps/rs841

    Google (for example): http://www.google.com/search?hl=en&q=GCH1 rs841

    Importantly, virtually no study is ever decisive until proven in the real world. Many studies lack validity (either statistically or otherwise), or are contradicted by other studies, or simply don't turn out to have relevance in real life, etc.

    Most importantly, remember that no SNP by itself causes disease, by definition. A SNP may predispose to disease, but it requires a combination of other factors (e.g., other SNPs, environment, diet, epigenetics, etc) to actually cause disease.

    Here are the 38 SNPs (note that I don't have any heterozygous results):

    rs841 G>A AA +/+

    rs41298442 T>C TT -/- (actual mutation)

    i5000652 A>G AA -/-

    rs41298440 G>A GG -/-

    rs752688 C>T TT +/+

    i5000639 G>A GG -/-

    i5000654 C>T CC -/-

    i5000643 G>C GG -/-

    i5000649 C>A CC -/-

    i5000644 C>T CC -/-

    rs17253591 C>T CC -/-

    rs10131232 G>A AA +/+

    rs17128021 G>A GG -/-

    rs4411417 T>C CC +/+

    rs2878168 G>A AA +/+

    rs17128028 C>T CC -/-

    rs2878169 G>T GG -/-

    i5000641 A>G AA -/-

    rs9671371 C>T TT +/+

    i5000651 T>G TT -/-

    i5000655 T>A TT -/-

    i5000642 A>G AA -/-

    rs17128033 C>T CC -/-

    rs7492600 G>T GG -/-

    rs12147422 T>C TT -/-

    rs3783637 C>T CC -/-

    rs8004018 A>G AA -/-

    rs10498472 T>G TT -/-

    rs998259 C>T CC -/-

    rs12885400 T>C TT -/-

    rs7147286 G>A AA +/+

    rs3783641 T>A AA +/+

    rs3783642 T>C CC +/+

    rs8017210 G>A AA +/+

    i5000650 C>T CC -/-

    rs56127440 G>A GG -/-

    i5000645 G>A GG -/-

    rs41298432 G>A GG -/-

    Edit: I almost forgot, 23andMe provides a 39th "intergenic" SNP for GCH1 as well, that I am heterozygous for:

    rs8007267 C>T CT +/-

    See: https://www.23andme.com/you/explorer/snp/?snp_name=rs8007267
     
    Last edited: Jan 25, 2015
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  13. Gondwanaland

    Gondwanaland Senior Member

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    Nan, myself, my husband (daltonics please apologize) @nandixon you have quite a few +/+ !

    rs841 G>A AA +/+ our 23andMe didn't test for it (n.a.)

    rs41298442 T>C TT -/- (actual mutation) TT TT

    i5000652 A>G AA -/- AA AA

    rs41298440 G>A GG -/- GG GG

    rs752688 C>T TT +/+ CC CC

    i5000639 G>A GG -/- (n.a.)

    i5000654 C>T CC -/- CC CC

    i5000643 G>C GG -/- GG GG

    i5000649 C>A CC -/- (n.a.)

    i5000644 C>T CC -/- CC CC

    rs17253591 C>T CC -/- (n.a.)

    rs10131232 G>A AA +/+ AG GG

    rs17128021 G>A GG -/- (n.a.)

    rs4411417 T>C CC +/+ TT TT

    rs2878168 G>A AA +/+ (n.a.)

    rs17128028 C>T CC -/- (n.a.)

    rs2878169 G>T GG -/- GT GG

    i5000641 A>G AA -/- (n.a.)

    rs9671371 C>T TT +/+ (n.a.)

    i5000651 T>G TT -/- TT TT

    i5000655 T>A TT -/- TT TT

    i5000642 A>G AA -/- (n.a.)

    rs17128033 C>T CC -/- (n.a.)

    rs7492600 G>T GG -/- GG GT

    rs12147422 T>C TT -/- TT CT

    rs3783637 C>T CC -/- CC CT

    rs8004018 A>G AA -/- (n.a.)

    rs10498472 T>G TT -/- (n.a.)

    rs998259 C>T CC -/- CT CT

    rs12885400 T>C TT -/- TT TT

    rs7147286 G>A AA +/+ GG AG

    rs3783641 T>A AA +/+ TT TT

    rs3783642 T>C CC +/+ CT CT

    rs8017210 G>A AA +/+ GG GG

    i5000650 C>T CC -/- CC CC

    rs56127440 G>A GG -/- GG GG

    i5000645 G>A GG -/- GG GG

    rs41298432 G>A GG -/- GG GG

    intergenic rs8007267 C>T CT +/- CC CC
     
    Last edited: Jan 25, 2015
    nandixon likes this.
  14. Mimi

    Mimi Senior Member

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    Medford, OR
    I haven't figured out how you get the major and minor alleles yet, but here is my data for comparison purposes. I'll edit it when I have more time:

    rs841 A or G
    AG

    rs41298442 C or T
    TT

    i5000652 A or G
    AA

    rs41298440 A or G
    GG

    rs752688 C or T
    CT

    i5000639 A or G
    GG

    i5000654 C or T
    CC

    i5000643 C or G
    GG

    i5000649 A or C
    CC

    i5000644 C or T
    CC

    rs17253591 C or T
    CC

    rs10131232 A or G
    AG

    rs17128021 A or G
    GG

    rs4411417 C or T
    CT

    rs2878168 A or G
    AG

    rs17128028 C or T
    CC

    rs2878169 G or T
    GG

    i5000641 A or G
    AA

    rs9671371 C or T
    CT

    i5000651 G or T
    TT

    i5000655 A or T
    TT

    i5000642 A or G
    AA

    rs17128033 C or T
    CC

    rs7492600 G or T
    GG

    rs12147422 C or T
    TT

    rs3783637 C or T
    CC

    rs8004018 A or G
    AA

    rs10498472 G or T
    TT

    rs998259 C or T
    CC

    rs12885400 C or T
    TT

    rs7147286 A or G
    AG

    rs3783641 A or T
    AT

    rs3783642 C or T
    CT

    rs8017210 A or G
    AG

    i5000650 C or T
    CC

    rs56127440 A or G
    GG

    i5000645 A or G
    GG

    rs41298432 A or G
    GG
     
  15. nandixon

    nandixon Senior Member

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    I just edited my post to add a 39th intergenic SNP I forgot about.
     
  16. Mimi

    Mimi Senior Member

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    Medford, OR
    thanks!
     
  17. Sea

    Sea Senior Member

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    NSW Australia
    Thanks for that nandixon. I am heterozygous for rs998259. Major allele for the rest
    With admittedly an equally cursory look I think I saw that several of the i numbers have pathogenic alleles.

    Not quite true. There are some snps that definitely cause disease because the letter substitution results in a change that prevents the gene from working properly. Thankfully most substitutions have no or minor effect, or are a duplicate pathway such that other genes can do the same job.

    Some examples that come to mind are the metabolic disorders such as Fatty Acid Oxidation Disorders, (eg SCAD, MCAD, VCAD, VLCADD, CPT1 & CPT2) and Organic Acidemias (eg GA1 & GA2). While these may be caused by large deletions/insertions in the gene they are also often caused by a single snp especially, but not always, homozygous
     
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  18. Valentijn

    Valentijn The Diabolic Logic

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    I have rs17253591 TT, which is pretty rare (0.1%), though less so among europeans (2%). I also have the rare versions of rs2878169 and rs10498472, but those are tightly linked to the other one.
     
    nandixon likes this.
  19. shoponl

    shoponl

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    nandixon,

    The ten +/+ you listed for the GCH1 gene are the same ones I have, and at least one other person in the GCH1discussions Yahoo group has the same ten too. So I'm wondering if the 3 SNPs in the GS224 genoset really represent a large genoset of SNPs that are all inherited together. What do you think?

    I used the LiveWello template here:
    https://livewello.com/library/gch1-pcbd1-pts-and-qdpr-mutations-depleting-bh4?author=markj

    I'm also wondering if this genoset could have effects on NO/ONOO even when phe and tyr plasma levels are within normal ranges (normal ranges implying adequate BH4). Any thoughts?

    ~judi
     
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  20. nandixon

    nandixon Senior Member

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    Hi Judi, That's pretty much correct because the genoset of 3 SNPs that Promethease gives as "GS224" actually contains representative members from two different haplotype blocks. (See: GTP Cyclohydrolase I Gene Polymorphisms Are Associated with Endothelial Dysfunction and Oxidative Stress in Patients with Type 2 Diabetes Mellitus) At least a couple of the 10 SNPs we share may just be coincidental though.

    I'm not sure how significant the GS224 genoset is without what may be, for example, certain epigenetic factors. It looks like it's detrimental in T2D (from the study I cited above), and it also looks like it's detrimental in coronary artery disease (from the Antoniades study). But for other people I'm not sure.

    Theoretically, the nitric oxide synthase enzymes might have a lower tolerance to an inadequate pool of BH4 than the hydroxylases that make the neurotransmitters. So yes there might be a nitric oxide (and thus peroxynitrite) problem even with normal levels of phenylalanine and tyrosine, for example.
     
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