• Welcome to Phoenix Rising!

    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

    To become a member, simply click the Register button at the top right.

SHMT mutations and whether to address

Messages
21
Location
near LA, California
Does one need to address SHMT mutations (2 are heterozygous on the MTHFRSupport report) when they have low normal iron (not high), SCFAs were high on a CDSA, and suberic and beta hydroxl methylglutaric acid were high normal as was one other fatty acid metabolite?





One of the SHMT1s was hetero and one of the SHMT2s was hetero.



If I do need to address it, what do I take to address it? I believe it has something to do with folinic acid.
 
Messages
15,786
Does one need to address SHMT mutations (2 are heterozygous on the MTHFRSupport report) when they have low normal iron (not high), SCFAs were high on a CDSA, and suberic and beta hydroxl methylglutaric acid were high normal as was one other fatty acid metabolite?
Not all SNPs are relevant. What were the actual names or rsID's for the SHMT SNPs?
 

Bluebell

Senior Member
Messages
392
Valentijn, I don't know what the MTHFRSupport site reports on, but for another thread today I looked at my 23andMe SHMT2 genes and these were the only 2 that came up in my 23andMe data.

The last column is my result, the second-to-last column is what the majority allele is.

On the second row, for that one the majority allele varies a lot by geography so I didn't put it in my table, but I *think* that in Europeans the majority allele is AG like mine.

Diana S., is the second one the one that you are heterozygous for, as I am?

SHMT2 rs12319666 G or T GG GG
SHMT2 rs34095989 A or G xx AG
 
Messages
15,786
SHMT2 rs12319666 G or T GG GG
SHMT2 rs34095989 A or G xx AG
Yeah, heterozygous for the 2nd one wouldn't mean anything. It's by far the most common genotype (allele combination) in Europeans. There's also no research on it at all, hence no reason to think it has any impact on the SHMT2 gene.

Heterozygous GT for the first one be more interesting, since that happens in about 1% of any population, with 0% showing up homozygous TT for the minority allele. The first one also results in a stop-gain mutation, which has an impact on the gene structure and is a lot more likely to affect how the gene functions.
 
Messages
21
Location
near LA, California
Valentijn, I don't know what the MTHFRSupport site reports on, but for another thread today I looked at my 23andMe SHMT2 genes and these were the only 2 that came up in my 23andMe data.

The last column is my result, the second-to-last column is what the majority allele is.

On the second row, for that one the majority allele varies a lot by geography so I didn't put it in my table, but I *think* that in Europeans the majority allele is AG like mine.

Diana S., is the second one the one that you are heterozygous for, as I am?

SHMT2 rs12319666 G or T GG GG
SHMT2 rs34095989 A or G xx AG

Yes, I'm heterozygous for the second one, like you.
 
Messages
15,786
SHMT1 is Rs9909104 and SHMT2 is Rs34095989
It looks as though rs9909104 C does indicate a mild dysfunction with the gene.

But rs34095989 lacks any research, so probably doesn't mean anything. And it definitely doesn't mean anything which we can figure out :D

SHMT is responsible for creating methylfolate and folinic acid, so it's possible you might be needing a bit of those.
 

Bluebell

Senior Member
Messages
392
It looks as though rs9909104 C does indicate a mild dysfunction with the gene.
SHMT is responsible for creating methylfolate and folinic acid, so it's possible you might be needing a bit of those.

Hmm, I am homozygous CC for SHMT1 rs9909104.

Only 4% of Europeans have that.

And Watsonbell. :p

---
Valentijn, is there any reason to take both folinic acid and methylfolate as supplements?
 

Bluebell

Senior Member
Messages
392
Hmm, I am homozygous CC for SHMT1 rs9909104.

Oh golly.

"what would become our most promising SNP (SHMT1 rs9909104) with ovarian carcinoma risk"
http://scholar.google.com/scholar?q=rs9909104

And ovarian cancer is what I'm concerned about at the moment (with the result of my CA-125 test).

"Each copy of the minor allele in SHMT1 intron 5 A>G (rs9909104) was associated with epithelial ovarian cancer [odds ratio (OR), 1.2; 95% confidence interval (95% CI), 1.0–1.4; P trend = 0.02; FPRP = 0.16] "
http://cancerres.aacrjournals.org/content/68/7/2498.short

So if I have CC on that, do I have 2 A>Gs? Does my odds ratio get even higher?

===
"Three SNPs in DNMT3A were associated with risk among multivitamin supplement users: 3′ untranslated region (UTR) C>G (rs13420827: OR, 0.8; 95% CI, 0.6–1.0; P interaction = 0.006; FPRP = 0.54), intron 6 G>A (rs11887120: OR, 0.8; 95% CI, 0.7–1.0; P interaction = 0.007; FPRP = 0.57), and intron 22 A>T (rs11695471: OR, 1.2; 95% CI, 1.0–1.5; P interaction = 0.01; FPRP = 0.66). These data extend previous findings from other cancers of a role for SHMT1 in ovarian cancer, and provide evidence that SNPs in methylation and DNA synthesis reactions are associated with risk of ovarian cancer. Interventions with modifiable factors such as multivitamin intake may reduce risk. "
same source as above

I have no report in 23andMe for the first rs number of these 3.

for the 2nd, rs11887120, I have TT -- what does this mean?
Does "G>A" mean if a C is changed to a T then the odds ratio of 80% applies (like a 20% less chance of getting ovarian cancer when you take a multivitamin?)
If both Cs are changed to Ts, does the odds ratio get better somehow, or stay the same?
TT is not too common, in the teens, I think I saw.

for the 3rd, rs11695471, I have TT --
Does an odds ratio of 1.2 mean that taking a multivitamin makes it more likely to get ovarian cancer? And are the odds even worse when it's two Ts instead of one?
TT in that one is pretty common, at least half, in the few populations looked at on dbSNP.

==
The rare allele of a tSNP in
NMI (rs11683487) showed evidence of association
with reduced risk of ovarian cancer (heterozygous odds ratio [OR] with 95%
confidence intervals [CI] 0.80 [95% CI 0.69-0.93] homozygous OR 0.87 [0.71-1.02],
P = 0.038)"
http://discovery.ucl.ac.uk/1310441/1/1310441.pdf

For rs11683487 I have TT.
It's in 18% of Europeans - is TT what she is calling "rare allele of a tSNP", and what's a "tSNP"?

Well, her doctoral thesis
Identifying Common Genetic Variants Associated With Disease Risk And Clinical Outcome In Epithelial Ovarian Cancer
is only 530 pages long, so i'll just skim it.
for a week or so :ill: .
 

Bluebell

Senior Member
Messages
392
Richvank discussed that a bit here: Methylation Pathway Analysis
Basically it can turn into methylfolate much more easily than folic acid, and might help as a bit of a buffer.

Thanks for finding that reference for me.

I had already read what Rich said about it, I just didn't know if you had read some external research about it.

The reason Rich recommended folinic acid was that it can turn into other forms of folate in the body, which methylfolate cannot do, apparently. "This is a buffer form of folate that most people can readily convert to other active forms of folate. Its role in the protocol is to supply these other forms while the methionine synthase reaction has still not come up to normal. This is particularly important for making new DNA and RNA for replacing cells." http://forums.phoenixrising.me/inde...ol-august-25-2012-revision.19050/#post-290885

As to why he had methylfolate in his protocol - "The function of this supplement in the protocol is to replenish the form of folate directly needed by the methionine synthase reaction, which is partially blocked. This form has been depleted by reactions with peroxynitrite, and some people are not able to convert other forms of folate into methylfolate readily." same source
 

nandixon

Senior Member
Messages
1,092
The reason Rich recommended folinic acid was that it can turn into other forms of folate in the body, which methylfolate cannot do, apparently.

No, methylfolate (5-MTHF) is converted to the other forms via either methionine synthase (gene = MTR), which makes tetrahydrofolate (THF) and of course methionine, or through the reversible MTHFR and SHMT reactions, which together can also make THF (in their reverse directions).

Rich recommended folinic acid because he thought the MTR reaction might not be working well in some people with CFS/ ME, not because methylfolate can't be converted into the other forms. Obviously, for people with the more serious combinations of MTHFR defects, the reverse reaction provided for by the MTHFR enzyme might be problematic, and so folinic acid might be needed, especially where both MTHFR and MTR (or MTRR) are impaired.

Too much folinic acid, though, can be bad for some people, by inhibiting SHMT and other enzymes, so it may have a narrow therapeutic window. (Though, you wouldn't know that from the Lundell study, which used massive quantities of folinic acid.)

Note that Wikipedia states that:

"Methionine synthase is the only mammalian enzyme that metabolizes N5-MeTHF to regenerate the active cofactor THF."

That's not exactly correct, of course, since the MTHFR reaction is reversible, and together with the reversible SHMT reaction can regenerate THF.
 

Bluebell

Senior Member
Messages
392
Rich recommended folinic acid because he thought the MTR reaction might not be working well in some people with CFS/ ME, not because methylfolate can't be converted into the other forms. .

I had realized this from the following part of what I quoted by him above
Rich: "{Folinic Acid's} role in the protocol is to supply these other forms while the methionine synthase reaction has still not come up to normal,"
but I was just taking a shortcut to say that it "can't". (I should have said, "It probably can't in those people who are the likely people who are concerned about their methylation difficulties, who are on this CFS/ME website, and who have gotten to the point with their symptoms where they are thinking about trying Rich's protocol" ! :) ):

A few days earlier, I wrote on another thread, "...it seems that the thinking is: Taking folinic acid at the same time as methylfolate can be a help to people because it gives the body a form of folate that the body can use instantly for certain things that the body cannot use the methylfolate form of folate for, at least not instantly. Because of that, when overall methylation is poor, giving methylfolate only, at first, can starve the body of some of the benefits of folate in general. (When overall methylation is good, then this is not so much of a concern.)" http://forums.phoenixrising.me/inde...est-for-genetic-data.19168/page-4#post-373795