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BH4 - GCH1 Question

Do you have a GCH1 mutation?

  • Yes

    Votes: 26 78.8%
  • No

    Votes: 7 21.2%

  • Total voters
    33

Mimi

Senior Member
Messages
203
Location
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.
 
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ahmo

Senior Member
Messages
4,805
Location
Northcoast NSW, Australia
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
 

Mimi

Senior Member
Messages
203
Location
Medford, OR
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.
 
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nandixon

Senior Member
Messages
1,092
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.
 

Mimi

Senior Member
Messages
203
Location
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.
 
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Mimi

Senior Member
Messages
203
Location
Medford, OR
How are you determining what constitutes a "mutation"? Which alleles of which SNPs are supposed to have a negative impact?
Hi Valentijn, I've deleted that part of my post so as not to confuse people by my own lack of understanding.
 

Gondwanaland

Senior Member
Messages
5,092
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
 
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ukxmrv

Senior Member
Messages
4,413
Location
London
rs10131232 AG

rs2878169 GT

rs7492600 GG

rs12147422 TT

rs3783637 CC

rs11158026 can't find

rs998259 CT

rs7147286 GG

rs3783642 CT
 

ukxmrv

Senior Member
Messages
4,413
Location
London
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.
 

nandixon

Senior Member
Messages
1,092
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
 
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Gondwanaland

Senior Member
Messages
5,092
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
 
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Mimi

Senior Member
Messages
203
Location
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
 

Sea

Senior Member
Messages
1,286
Location
NSW Australia
Thanks for that nandixon. I am heterozygous for rs998259. Major allele for the rest
With just a cursory look, I think rs41298442 might be the only true mutation 23andMe provides, i.e., one that definitively causes disease.
With admittedly an equally cursory look I think I saw that several of the i numbers have pathogenic alleles.

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.
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
 
Messages
15,786
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.
 
Messages
99
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.

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
 

nandixon

Senior Member
Messages
1,092
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?
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 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
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.