Confused about MTHFR SNP

[determined]

I have found some conflicting information regarding the SNPs that are responsible for the lesser functional ability of MTHFR.

I had Promethease analyze my 23andme SNPs and it said that I have the CC version of both rs1801133 and rs1801131. The analysis said that I "have trouble metabolizing common vitamin pills."

However, I found this article with the following:

The most-studied polymorphism is the
677T)C (rs1801133) in exon 5 of the 5,10-methylenetetrahydrofolate
reductase (MTHFR [MIM 607093]) gene.
The 677T variant results in an thermolabile enzyme that
is less effective in the conversion of 5,10-methylenetetrahydrofolate
to 5-methyltetrahydrofolate.20 Accordingly,
individuals with the 677T variant have higher homocysteine
concentrations as well as lower genomic DNA methylation.
21,22

So it is saying that the TT version is the ineffective one. The article is from:

http://www.sph.umich.edu/csg/abecasis/publications/pdf/Am.J.Hum.Genet.vol.84-pp.477.pdf

My understanding is that the C replacing T version is the ineffective one. Does anyone have any idea which is right?

 

[rwac]

You have the normal version of Rs1801133 (677C), but the ineffective version of Rs1801131 (1298A>C).

See: http://www.pharmgkb.org/do/serve?objId=PA165110385

 

[determined]

Thank you very much rwac! Okay, that makes sense now.

 

[lucyhem]

I have only been tested for the, MTHFR 677 gene which I am homogenous. I have two variants in that gene. I noticed that this gene is not on the list of the SNP's that Yasko tests for. I am confused about that. I am trying to get oriented to start the protocol and wonder if it will be important to have those other genes tested before beginning. I had an initial dramatic improvement on 7mg Deplin. Then I think my methyl pathway was overwhelmed and the benefit disappeared. Now I understand I need to start very small. I do plan on getting the Methylation pathways test. Any thougths or suggestions?
Lucy

 

[determined]

I'm not sure you have to wait for any more information, given that you have the 677 AND you had a dramatic response to deplin.

Remember that the deplin doses are HUGE compared to those that Rich recommends. I am still having a big effect from a "homeopathic" dose (I take a speck of a 200mcg tablet, dilute it in a cup of water, then take 1 teaspoon of it.

I think slower is better, especially if you have been ill a long time.

 

[lucyhem]

dear determined,
Thank you for your response. That is so cool you have found your homeopathic dose. I may try that. Are you taking other supplements on the protocol as well?
Are the other supplements meant to help with this issue of the methylation pathway being blocked?
Maybe you can help me sort out something else. After the Deplin stopped working for me I backed off, took a break and then started with Methylfolate in much smaller doses, then sublingually. I never reproduced those intial dramatic results. I did not have exaccerbations I dont think. I am not sure what the might mean or how to work with that information. I am thinking that the methlyation pathways were still overwhelmed and needed time to clear out.
My response to Deplin was immediate. I am wondering how others have evaluated whether the methylfolate was working for them. Is it immediate or gradual on a smaller dose?

 

[determined]

Hi lucyhem,
Energy-wise, my improvement on the tiny doses of methylfolate and mB12 were gradual. But I did have a period of time, fairly early on, (maybe even within a few days, I can't remember...) in which I enjoyed a wonderful "mental clarity." Things that have seemed overwhelming for YEARS, like cleaning out some cabinets, suddenly seemed very doable.

So far I am only doing the methylfolate and mB12.

Here is a link to a discussion about "why supplements stop working."

http://forums.phoenixrising.me/show...nts-medication-stop-working&highlight=taurine

 

[lucyhem]

Has that mental clarity remained or was that a passing phenomena? I will be interested in your link as I have had several remarkable responses to substances that then passed.
Lucy

 

[determined]

The exceptional mental clarity didn't last; Rich has mentioned that perhaps the short-lived improvements that we often get when we start something can mean that it was "rate-limiting" and supplementing it allows metabolism to run more smoothly for a bit, and then something else is missing and becomes rate-limiting.

I think it's also possible that there is a shift in the immune system when we start something, perhaps due to a change in the intestinal microbiome. Several of the things that have really helped me long-term have certainly affected the microflora, such as doxycycline (but it is also an immune modulator, so it's not clear to me why it helps) and calcium d-glucarate.

So, about four months into my tiny dose of methylfolate and mB12, my chemical sensitivities seem more under control and back where they were before I started (they got worse for a month or so with the supplements), but foods seem to bother me more than they had been.

I'll report back at the end of June....I have a very physically demanding schedule and I am eager to see if my increased energy holds.

 

[Waverunner]

rwacs site is down currently. Can anyone tell me if TT or GG is the ineffective version of rs1801131 when looking at 23andme raw results?

When rs1801133 is AG/CT, does this mean that it's working 50%?

EDIT: TT is the working version, correct?

 

[determined]

Hi Waverunner,
For rs1801131 the "normal" condition is TT (or AA depending on which strand of DNA they are reading - in the double stranded DNA molecule, A binds with T and C binds with G in a complementary fasion - so if you know one strand's letter at a particular location, you automatically know the other strand's letter at that same location).

So a SNP of this normal condition is GG (or CC). Does this mean that if you have the genotype TG, the enzyme is only 50% active??

No. Sometimes such mutations are "silent." That is, they have no effect on the function of the enzyme. This is contrast to a mutation in a BRCA gene, for example. In some cases of BRCA mutations, the protein produced from that gene is completely nonfunctional. But I don't believe it's completely clear what these variations in the MTHFR enzymes mean.

I myself am CC (GG). There are some research articles suggesting some problems with the various SNPs 23andme tests for, but this kind of research is in its infancy, in my opinion. Having said that I have had a big effect from adding the activated form of folate that Rich suggests. Is it because of a genetic inability to metabolize dietary folate, or is it a functional deficit? I don't think we can know, but for me, it just makes sense to continue on the methylation supplements and see where it takes me.....

 

[Waverunner]

Thanks a lot for your answer, determined. For me it seems that CFS is not caused by our genetics but our genetics likely determine what symptoms we get. I'd give everything to know what causes CFS.

 

[determined]

I would love to live to see a real understanding of this disease too. It's so complicated!

There must be something that ties everything together, but I do agree that our particular genetics and maybe our SNPs determine how hard we are hit and in what way.

 

[Waverunner]

As you stated, there must be something that ties everything together. The cause must be hiding very well, either it's very, very small or it's in the brain or CNS because it's so hard to look there. Even if XMRV turns out to be nothing at all, I'm still optimistic. The medical field made a lot of progress during the last years.

 

[drex13]

Eliminating the guesswork...

You know, I'm thinking of just biting the bullet and paying the $495 for the Yasko nutrigenomic test and eliminating all of this guesswork with regards to the Methylation SNP's. I know it's alot more than the 23andme testing (which I have done), but you get an explanation of the SNP's plus recommendations on which supplements you should be taking specifically for methylation. There is a sample test w/ recommendations on the Yasko site, but I still can't figure out exactly how to apply it to me.

 

[determined]

I've thought about testing too, Drex13. But I'm with you. I don't have a lot to spend on it, and I'm not sure that there would be any practical result. I do appear to have an issue with methylation, based on my dramatic results to the tiniest amount of supplementation. Please make a BIG annoucement, if you decide to do it, and let us know what you think of the information.

 

[drex13]

I've thought about testing too, Drex13. But I'm with you. I don't have a lot to spend on it, and I'm not sure that there would be any practical result. I do appear to have an issue with methylation, based on my dramatic results to the tiniest amount of supplementation. Please make a BIG annoucement, if you decide to do it, and let us know what you think of the information.

I actually found a doctor here in Ohio (Toledo) who is a cardiologist into Integrative Medicine who uses the Yasko testing and as luck would have it, he is on my insurance. Don't know if the nutrigenomic testing would be covered or not, but it sounds like he has Dr. Yasko do the interpretation and recommendations and then makes some recommendations of his own. Here' s a link to part of his site, with a methylation diagram and a patient example , etc... that I got from somewhere.

http://www.heartfixer.com/AMRI-Nutrigenomics.htm

 

[determined]

Wow, how nice that would be to have a doctor who actually knows more than a little about all this. Best of luck - and please, let us know what he says.

 

[Johnmac]

So, about four months into my tiny dose of methylfolate and mB12, my chemical sensitivities seem more under control and back where they were before I started (they got worse for a month or so with the supplements), but foods seem to bother me more than they had been.

I'll report back at the end of June....I have a very physically demanding schedule and I am eager to see if my increased energy holds.

Would be interested to hear how you ended up, as I'm just starting the methylfolate and mB12.

Thanks,

John