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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. nandixon

    nandixon Senior Member

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    I'm hoping people with 23andMe results will compare their results to mine below and post if they see a problem or not. Mine indicate a potential problem that might be applicable to others, and I think it would be good to know how prevalent this is in the ME/CFS community. Thanks!

    As previously mentioned on the thread* for the DHFR SNPs, GTP cyclohydrolase I (GTPCH or GCH1) is the rate-limiting enzyme in the body's synthesis of tetrahydrobiopterin (BH4). [*http://forums.phoenixrising.me/index.php?threads/snps-for-dihydrofolate-reductase-dhfr.19563/]

    BH4 is important in the production of neurotransmitters and also for regulation of the enzyme nitric oxide synthase (NOS). NOS can potentially become dysregulated ("uncoupled") when BH4 is deficient and produce too much nitric oxide and superoxide, leading to peroxynitrite and, theoretically, exacerbating the chronically high levels of oxidative stress that are seen in CFS/ME.

    Mutations in GCH1 can cause a deficiency of BH4, and so seems worth exploring to see if it may be compounding the problems some people also have in the methylation cycle genes, i.e., MTHFR, MTRR, CBS, etc.

    I don't see where Amy Yasko has specifically addressed this gene in the work she's done primarily with autistic children, who appear to have similar methylation cycle problems. Perhaps it's not widely relevant there, or for us either, but every possibility we can at least eliminate brings us one step closer to finding a treatment for those who don't fully respond to a methylation protocol. Note that Yasko does place importance on BH4 via the MTHFR A1298C marker (rs1801131).

    If Martin Pall, proponent of the nitric oxide/peroxynitrite theory for CFS/ME (and MCS, etc), was testing patients similarly to Yasko, I assume examination of the GCH1 gene would be at or near the top of his list. Note that this enzyme requires zinc as a cofactor.

    I've given what I believe to be the normal (common) results for the alleles in parentheses. These SNPs are listed in the same order SNPedia gives here:
    http://snpedia.com/index.php/GCH1

    GCH1 SNPs:
    rs10483639 +/+ CC (GG) (part of a 3 SNP haplotype w/ rs3783641 & rs8007267 associated w/ reduced levels of BH4; 2% frequency from openSNP)
    rs104894433 thru -45 No Data
    rs12147422 -/- TT (TT)
    rs137852633 No Data
    rs17738966 -/- GG (GG)
    rs2878172 +/+ GG (AA) (17% frequency)
    rs3783637 -/- CC (CC)
    rs3783641 +/+ AA (TT) (part of haplotype w/ rs10483639 & rs8007267; "0%" frequency)
    rs41298442 -/- TT (TT)
    rs4411417 +/+ CC (TT) (higher tolerance to pain; 2% frequency)
    rs7142517 -/- CC (CC)
    rs752688 +/+ TT (CC) (2% frequency)
    rs8007201 No Data
    rs8007267 -/+ CT (CC) (part of haplotype w/ rs10483639 & rs3783641)
    rs841 +/+ AA (GG) (associated w/ lower novelty seeking; 3% frequency)
    rs998259 -/- CC (CC)
    rs7147286 +/+ AA (GG) (not listed on SNPedia; 10% frequency)

    GCH1 activity is regulated by GTP cyclohydrolase I feedback regulator (GCHFR). GCHFR stimulates GCH1 in the presence of L-phenylalanine. 23andMe gives one result for this gene, which I'm negative for:

    rs2016546 -/- GG (GG)
    roxie60 likes this.
  2. merylg

    merylg Senior Member

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    My GCH1 SNPs:
    rs10483639...C or G...GG
    rs12147422...C or T...TT
    rs17738966...A or G...GG
    rs2878172.....A or G...AA
    rs3783637...C or T... CC
    rs3783641... A or T... TT
    rs41298442... C or T... TT
    rs4411417... C or T... TT
    rs7142517....A or C....CC
    rs752688... C or T... CC
    rs8007267...C or T...CC
    rs841... A or G... GG
    rs998259... C or T... no call
    rs7147286... A or G... GG

    rs2016546... G or T... GG
  3. roxie60

    roxie60 Senior Member

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    I have added mine and inserted nandixon's (please verify I transfered your info correctly). I don't know if the +/- is of value so I added them but will copy a list without them cause I think it is easier to read just not sure how it affects interpretation. I think we are looking for commonality for PWCFS/ME and where we specifically might have issues. Let me know if I'm wrong. I know these just mean there is the possibility of biochemical issues, not fact (personal experience will drive your conclusions, not just the data IMO). So with three of us, based on data alone, it looks like nandixon and I may have some BH4 cycle issues (I'm no expert, just trying to learn to interpret).

    I also added the comment from SNPedia.com http://www.snpedia.com/index.php/GCH1 regarding this gene GCH1:
    GCH1 is the gene responsible for the first, and rate-limiting, step in producing tetrahydrobiopterin (BH4) which is used as a cofactor in the production or conversion of several neurotransmitters.
    Please note that reference GCH1 sequences use the reverse strand. Many journal articles will use minus orientation when reporting results, even for cases where the dbSNP orientation is plus. Some of the significant SNPs in this gene have ambiguous flips which can make interpreting things difficult.
    GCH1 activity is regulated by GCHFR.


    roxie60 GCH1 SNPs are in ORANGE, I have added the 'believed common' to the beginning of the list, then nandixon, then Merylg, then roxie60:

    1=(common), 2=nandixon, 3=merylg, 4=roxie60

    rs10483639...C or G...(GG),CC+/+,GG, GG
    rs12147422...C or T...(TT),TT,TT, CT+/-
    rs17738966...A or G...(GG),GG,GG, GG
    rs2878172.....A or G...(AA),GG+/+,AA,AG-/+
    rs3783637...C or T... (CC),CC,CC,CT-/+
    rs3783641... A or T... (TT),TT,TT, no call
    rs41298442... C or T... (TT),TT,TT,TT
    rs4411417... C or T... (TT),CC+/+,TT,TT
    rs7142517....A or C....(CC),CC,CC,AC+/-
    rs752688... C or T... (CC),TT+/+,CC,CC
    rs8007267...C or T...(CC),CT+/-,CC,CC
    rs841... A or G...(GG),AA+/+, GG,GG
    rs998259... C or T...(CC),CC, no call, CC
    rs7147286... A or G...(GG),AA+/+, GG,AG+/-
    rs2016546... G or T... (GG),GG,GG,GG

    1=(common), 2=nandixon, 3=merylg, 4=roxie60

    rs10483639...C or G...(GG),CC,GG, GG
    rs12147422....C or T...(TT),TT,TT, CT
    rs17738966...A or G...(GG),GG,GG, GG
    rs2878172.....A or G...(AA),GG,AA,AG
    rs3783637....C or T... (CC),CC,CC,CT
    rs3783641.... A or T... (TT),TT,TT, no call
    rs41298442... C or T.. (TT),TT,TT,TT
    rs4411417.... C or T... (TT),CC,TT,TT
    rs7142517....A or C....(CC),CC,CC,AC
    rs752688..... C or T... (CC),TT,CC,CC
    rs8007267.....C or T...(CC),CT,CC,CC
    rs841............ A or G...(GG),AA, GG,GG
    rs998259...... C or T...(CC),CC, no call, CC
    rs7147286... A or G...(GG),AA, GG,AG
    rs2016546... G or T... (GG),GG,GG,GG
  4. roxie60

    roxie60 Senior Member

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    Because of the comment regarding the 'flips', it maybe be difficult to know if the orientations we have used are correct. nandixon, are you confident on your orientation calls (+'s and -'s)?

    For example: rs4411417 +/+ CC (TT) (higher tolerance to pain; 2% frequency) - is the comment for someone with the common orientation or the uncommon? Man this stuff is mind boggling.....
  5. roxie60

    roxie60 Senior Member

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    sorry nan, I see where you also posted teh SNPedia info on GCH1, did not mean to dup.
  6. roxie60

    roxie60 Senior Member

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    added the tag list for each person so far with data.

    nandixon, I am curious I see you are showing in your sig GCH1+/+, how did you determine it was +/+? Is there a method/rule or did you just notice you had a lot of +/+ and made the decision on your own?
  7. alex3619

    alex3619 Senior Member

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    I think this line of thinking could be very important, not just for those with abnormal snps but for most ME patients. I am increasingly focussing on cAMP, and its one factor that drives GCH1 production. Factors including phosphodiesterase-4 are possibly upregulated in ME (this is only an hypothesis at this point) and result in reduced cAMP, leading to memory and enzyme issues as cAMP is critical to many pathways.

    I see genetic abnormalities on these paths possibly increasing the impact, but not necessarily causal, for many of these issues.
  8. nandixon

    nandixon Senior Member

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    Hi roxie,
    I'm homozygous for two of the three SNP's and heterozygous for the third that constitute what's called the gs224 genoset (i.e., a haplotype consisting of rs10483639, rs3783641 & rs8007267), which is associated with reduced levels of BH4. So I have 5 of the 6 risk alleles associated with gs224. I'm also homozygous for all of several additional SNP's in the GCH1 gene that make up a larger haplotype that includes gs224. So I'm guessing I'm effectively positive (+/+) for gs224.

    Looking at your results, I wouldn't think you're likely to have a problem with GCH1.

    There's a discussion group for gs224 here:
    http://health.groups.yahoo.com/group/GCH1discussions/
    roxie60 likes this.
  9. roxie60

    roxie60 Senior Member

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    I kinda thought the same based on SNPs but based on test results I still wonder if BH4 is having issues since nearly all my neurotransmitter test (90%) are subnormal.
  10. triffid113

    triffid113 Day of the Square Peg

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    I had the Yasko panel, not 23andme so don't know the rate-limiting step in BH4 production, but my father died of no detectable level of BH4 due to MTHFR 1298CC (homozygous) and CBS +/- (two hetero). I want to alert everyone to the fact that low BH4 does not by far only affect neurotransmitter production, but also affects whether or not you can make UREA. If you cannot and go on dialysis, then you die of herat disease, and you have a far greater risk of dying promptly if you have low albumin (<4.0 due to you can't handle it due to these genes). I myself am hetero for MTHFR 1298 AC and have 2 CBS +/+, so I am scared into taking BH4 supplements. I had my father's biopterin level run by Metametrix lab and got it 2 days before he had a heart attack. I got the genetic test resulst 2 days after he died.
  11. Bluebell

    Bluebell Senior Member

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    Roxie, I noticed that NanDixon in her original post said that she was AA for rs3783641, whilst you have her as TT here in your chart.

    (That was the only one I compared between your chart and her original post, and I did that because of what she said later in the thread about her being abnormally homozygous for rs3783641 - which didn't make sense to me at first, given the TT that appeared in your chart for her, so I went back to her first post to doublecheck.)
    roxie60 likes this.
  12. PennyIA

    PennyIA Senior Member

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    I didn't have several of these on 23andme... but have documented the ones that aren't common:

    My GCH1 SNPs:
    rs3783641 (TT) AT
    rs998259 (CC) CT
    rs7147286 (GG) GT

    So, these three at minimum are heterozygous.

    I'm also homozygous A1298C which meant that I was thinking I would need something to help work with my levels.
  13. roxie60

    roxie60 Senior Member

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    I will edit my post if possible and correct but I thought I just copied what was already done and just added mine....thanks I will take another look I've responded to so many of the tracking SNP lists I need to refresh if I was the original author of the list, if so I will correct based on what you caught.

    Yep I did it, I'll correct it
  14. Bluebell

    Bluebell Senior Member

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    Thank you Roxie60 for making that change!

    ====
    As for this list of GCH1 rs numbers, I have all the "majority" alleles as designated in this thread, except for:

    rs7142517 -- I have AC
    rs998259 -- I have CT

    However, I *think* I saw this afternoon on the DBSnp website that in the European populations they checked for those 2 rs numbers, my alleles show up in 40 to 50+ % of those groups, so my results aren't uncommon.
  15. Bluebell

    Bluebell Senior Member

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    What supplements are good for BH4, Triffid113?

    I possibly knew what BH4 was at one point this summer, but now after a number of weeks away from the Phoenix Rising subject matter(s), I have no idea. :ill:

    I am heterozygous for MTHFR 1298 and have one +/- CBS thing, although I seem to have most of the majority alleles on GCH1 and DHFR.

    Ben Lynch cautions on BH4 direct supplementation: http://mthfr.net/forums/topic/bh4-supplement-for-a1298c/
    "There are ways to increase BH4 safely – without supplementing directly with biopterin.
    The biggest gains in increasing biopterin are:
    - decreasing inflammation
    - decreasing infections
    - – - both of these decrease neopterin which in turn increases biopterin formation. When neopterin is elevated, biopterin typically is decreased.
    - decreasing ammonia levels
    - adding methylfolate, iron, vitamin C, magnesium, b6 and others.
    It is always best to support a cycle with the necessary precursors rather than supplementing directly with the end product."
  16. roxie60

    roxie60 Senior Member

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    Bluebell sorry but I reckon too much time has passed so I am unable to correct Nan's value for 641. So if anyone recreates my table above where I tired to add everyone up to that point please edit the snp identified by Bluebell. Thx.
  17. roxie60

    roxie60 Senior Member

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    This stuff is mind boggling. I have two BH4 where I am homozyg (the ones in Yasko's methylation list) so I was expecting to have more issues with GHC1. Many are hetero but none are homozyg risk alleles.
  18. triffid113

    triffid113 Day of the Square Peg

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    Here is a list I made one time about things that raise or lower BH4. You can do your own web search...maybe science knows a few more things by now.

    Things that raise BH4
    · Methylfolate
    · Vitamin C
    · Niacin, niacinamide
    · Saunas
    · Estrogen
    · Insulin (normal/low blood sugar) [5]
    · Possibly helpful: purine GTP (BH4 can be made from it)


    Things that lower BH4
    · Genetic polymorphism MTHFR A1298C
    · High protein (Ammonia -- 2 BH4 required to eliminate 1 NH3)
    · ROS (radical oxygen species)
    · Salt
    · High blood sugar (due to oxidative stress)
    · Aspirin (interferes with folate absorption)
    · Excessive exercise? (Protein breakdown into ammonia)
    · Hypothyroid (oxidative stress)
    · Lithium, if it causes hypothyroid (it can)
    · Hypopituitary (causes oxidative stress)
  19. jepps

    jepps

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  20. nandixon

    nandixon Senior Member

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