MTHFS defect (folinic acid intolerance) - request for genetic data

[nandixon]

In January, Rich asked people to share their 23andMe results for the MTHFS gene to see if we can sort out which SNP or SNPs may be detrimental in ME/CFS. I didn't see where anyone responded. (You can find your MTHFS results by going to https://www.23andme.com/you/explorer/ and logging in and entering "MTHFS" for the gene name.)

It's important people contribute so we can try to figure out when folinic acid should be supplemented or avoided for certain people as part of a methylation protocol.

I may be intolerant to folinic acid (seems to cause exacerbation of fatigue, irritation of taste buds) and so am providing my DNA results. We need MTHFS results from as many other people as possible, though, whether intolerant or not.

If you could also include the one SHMT result that Yasko tests for, that may be helpful also. I'm heterozygous (AG) for that SNP (SHMT1 C1420T rs1979277), and the first day I took folinic acid it helped, as might be expected, but then I seemed to gradually get worse over several days (800-1600 mcg/day).

Below are Rich's personal MTHFS results with mine next to his in parentheses (he volunteered to be the DNA "standard"). At the time Rich was tested, 23andMe only gave results for 22 SNPs. They gave 24 for me. (36 are known?) There was only one instance of a flip in homozygosity between Rich's results and mine, rs7177659, and I discuss it after:

MTHFS rs8923 C or T CT (TT) [Rich is "CT"; I'm "TT"]
MTHFS rs2733103 C or T CC (CT)
MTHFS rs16971427 A or C AA (AA)
MTHFS rs655473 A or G AA (AA)
MTHFS rs17284990 C or T TT (CT)
MTHFS rs16971450 A or G AA (AA)
MTHFS rs6495446 C or T CT (CC)
MTHFS rs7177659 A or C CC (AA)***
MTHFS rs6495449 A or G GG (GG)
MTHFS rs17285431 A or C AC (AA)
MTHFS rs6495451 C or T CT (CC)
MTHFS rs2586154 A or G GG (AG)
MTHFS rs12899781 G or T GT (TT)
MTHFS rs16971478 A or G AA (AA)
MTHFS rs2586153 C or T CC (CT)
MTHFS rs2562744 A or C AA (AC)
MTHFS rs2733106 A or G AA (AG)
MTHFS rs12438477 A or C CC (CC)
MTHFS rs12898642 C or T CT (TT)
MTHFS rs2586182 A or C AA (AC)
MTHFS rs2733088 A or G AG (AG)
MTHFS rs12440798 C or T CC (CC)

My two additional results:
MTHFS rs685487 A or G (GG)
MTHFS rs8033649 A or C (CC)

We're not likely to be so lucky right away that rs7177659 is the "bad" SNP, but it's interesting because having the hetero version (AC) for that SNP actually seems to be "normal" (58% frequency according to openSNP) and apparently results in a 29% decrease in cardiovascular disease risk compared to the homo versions (AA/CC). (This is from a May 2012 publication: http://jn.nutrition.org/content/early/2012/05/28/jn.111.157180.abstract - I don't have access to the full text; it's not mentioned in the abstract.)

So with respect to that SNP it might be that I have a detrimental down-regulation of MTHFS and Rich has a detrimental up-regulation (or vice versa). A down-reg would cause a build up of folinic acid and thus inhibition of SHMT (and several other enzymes outside the methylation cycle as well) and create an intolerance to supplementation. An up-reg can cause an increased turnover rate and depletion of cellular folate. Note: The C allele - what Rich has two copies of - is the ancestral (wild type) allele according to the NCBI data page.

Hopefully, if enough people contribute, we can figure out which SNP(s) is/are problematic. Thanks!

 

[richvank]

Thanks for posting this, nan. It will be interesting to see if this SNP holds up as the key problem in folinic acid metabolism for people who have difficulty with it.

I just posted a query to the 23andme community about this SNP in connection with folinic acid tolerance.

Best regards,

Rich

 

[Gestalt]

What exactly is the specific purpose of taking Folinic Acid? What pathways does it affect, and why does it help some people, and why might an excess in others be harmful?

 

[richvank]

Hi, Gestalt.

Folinic acid is a buffer or storage form of folate that can be converted to other forms readily in most people.
The reason for including it in the simplified methylation protocol is that it can supply forms of folate needed to make new RNA and DNA while the methionine synthase enzyme is still running its reaction slowly. This reaction is fed directly by methylfolate, but until it goes through the reaction to produce tetrahydrofolate, it can't be used for forming other folates.

In order to use folinic acid a person must have a normally functioning MTHFS enzyme (not the same as MTHFR). If this enzyme is slow for genetic reasons, folinic acid can build up. and that will inhibit the SHMT reaction, which in turn will inhibit the normal production of MTHF, which in turn will hinder formation of DNA and formation of methylfolate.

According to Freddd, he cannot tolerate folinic acid, and there seem to be some others who can't, also. It would be helpful to pin down what SNP or SNPs are responsible for this.

Best regards,

Rich

 

[nandixon]

Hi Gestalt,

With your +/+ result for SHMT1, it could be ideal for you to participate in this "study." In theory, you may be needing to supplement with some folinic acid, because that's one of the two primary products SHMT makes (the other being methylene THF, which is used by MTHFR to make 5-methylfolate, and also by TYMS to make thymidine). Yet if your MTHFS is not working well, i.e., not doing a good job converting folinic acid to methenyl THF (different than methylene THF) then you might be pretty sensitive to supplementing with folinic acid - because an excess will inhibit SHMT (folinic acid is both a product of SHMT and an inhibitor of that same enzyme).

Perhaps people are mostly only going to be sensitive to folinic acid when they have defects in both SHMT1 and MTHFS, but folinic acid also inhibits other enzymes, including the mitochondrial version of SHMT, which is encoded by the SHMT2 gene. (SHMT1, which Yasko tests for, is the cytoplasmic version.)

So if, for example, you're not sensitive to folinic acid, then perhaps your MTHFS SNPs will be more closely aligned with Rich's, or with mine if you are.

BTW, in theory, P-5-P and zinc should increase the activity and quantity of SHMT. Too much vitamin A (not beta-carotene) may decrease it.

The book "Nutrient-Gene Interactions in Cancer" gives more detail about all of the above (SHMT & folinic acid). Available as a Google book, pages 218-222 are free.

 

[Gestalt]

Ok here are my 23andMe results:

Page 1 of 1
GenePosition SNP Versions Gestalt's Genotype
MTHFS, ST20-MTHFS 80136129 rs685487 A or G AG
MTHFS, ST20-MTHFS 80136288 rs8033649 A or C CC
MTHFS, ST20-MTHFS 80137560 rs8923 C or T TT
MTHFS, ST20-MTHFS 80138571 rs2733103 C or T CC
MTHFS, ST20-MTHFS 80138745 rs16971427 A or C AA
MTHFS, ST20-MTHFS 80141997 rs655473 A or G AA
MTHFS, ST20-MTHFS 80144197 rs17284990 C or T CT
MTHFS, ST20-MTHFS 80154571 rs16971450 A or G AA
MTHFS, ST20-MTHFS 80154982 rs6495446 C or T CC
MTHFS, ST20-MTHFS 80158042 rs7177659 A or C AA
MTHFS, ST20-MTHFS 80158159 rs6495449 A or G GG
MTHFS, ST20-MTHFS 80162265 rs17285431 A or C AA
MTHFS, ST20-MTHFS 80164053 rs6495451 C or T CT
MTHFS, ST20-MTHFS 80165368 rs2586154 A or G AG
MTHFS, ST20-MTHFS 80168282 rs12899781 G or T TT
MTHFS, ST20-MTHFS 80171971 rs16971478 A or G AA
MTHFS, ST20-MTHFS 80172133 rs2586153 C or T CC
MTHFS, ST20-MTHFS 80174388 rs2562744 A or C CC
MTHFS, ST20-MTHFS 80177687 rs2733106 A or G AA
MTHFS, ST20-MTHFS 80178283 rs12438477 A or C AC
MTHFS, ST20-MTHFS 80182050 rs12898642 C or T CT
MTHFS, ST20-MTHFS 80183766 rs2586182 A or C AC
MTHFS, ST20-MTHFS 80184657 rs2733088 A or G GG
MTHFS, ST20-MTHFS 80186340 rs12440798 C or T CT

 

[nandixon]

Thanks Gestalt. I've added your results to the right of mine which are to the right of Rich's. If you turn out to be intolerant to folinic acid, then I guess rs7177659 is still favored as being the bad SNP:

MTHFS rs8923 C or T CT (TT) (TT)
MTHFS rs2733103 C or T CC (CT) (CC)
MTHFS rs16971427 A or C AA (AA) (AA)
MTHFS rs655473 A or G AA (AA) (AA)
MTHFS rs17284990 C or T TT (CT) (CT)
MTHFS rs16971450 A or G AA (AA) (AA)
MTHFS rs6495446 C or T CT (CC) (CC)
MTHFS rs7177659 A or C CC (AA) (AA)***
MTHFS rs6495449 A or G GG (GG) (GG)
MTHFS rs17285431 A or C AC (AA) (AA)
MTHFS rs6495451 C or T CT (CC) (CT)
MTHFS rs2586154 A or G GG (AG) (AG)
MTHFS rs12899781 G or T GT (TT) (TT)
MTHFS rs16971478 A or G AA (AA) (AA)
MTHFS rs2586153 C or T CC (CT) (CC)
MTHFS rs2562744 A or C AA (AC) (CC)
MTHFS rs2733106 A or G AA (AG) (AA)
MTHFS rs12438477 A or C CC (CC) (AC)
MTHFS rs12898642 C or T CT (TT) (CT)
MTHFS rs2586182 A or C AA (AC) (AC)
MTHFS rs2733088 A or G AG (AG) (GG)
MTHFS rs12440798 C or T CC (CC) (CT)

My two additional results:
MTHFS rs685487 A or G (GG)
MTHFS rs8033649 A or C (CC)

Hopefully other people will add their results.

 

[anne_likes_red]

I've added mine, including the extra two.
FWIW I find folinic acid beneficial, it seems to improve my sleep.
Anne.

MTHFS rs8923 C or T CT (TT) (TT) (TT)
MTHFS rs2733103 C or T CC (CT) (CC) (CT)
MTHFS rs16971427 A or C AA (AA) (AA) (AA)
MTHFS rs655473 A or G AA (AA) (AA) (AA)
MTHFS rs17284990 C or T TT (CT) (CT) (TT)
MTHFS rs16971450 A or G AA (AA) (AA) (AA)
MTHFS rs6495446 C or T CT (CC) (CC) (CC)
MTHFS rs7177659 A or C CC (AA) (AA) (AA)***
MTHFS rs6495449 A or G GG (GG) (GG) (AG)
MTHFS rs17285431 A or C AC (AA) (AA) (AC)
MTHFS rs6495451 C or T CT (CC) (CT) (CT)
MTHFS rs2586154 A or G GG (AG) (AG) (GG)
MTHFS rs12899781 G or T GT (TT) (TT) (GT)
MTHFS rs16971478 A or G AA (AA) (AA) (AA)
MTHFS rs2586153 C or T CC (CT) (CC) (CT)
MTHFS rs2562744 A or C AA (AC) (CC) (AC)
MTHFS rs2733106 A or G AA (AG) (AA) (AG)
MTHFS rs12438477 A or C CC (CC) (AC) (AC)
MTHFS rs12898642 C or T CT (TT) (CT) (CT)
MTHFS rs2586182 A or C AA (AC) (AC) (AA)
MTHFS rs2733088 A or G AG (AG) (GG) (AG)
MTHFS rs12440798 C or T CC (CC) (CT) (CC)

My two additional results:
MTHFS rs685487 A or G (GG) (AG)
MTHFS rs8033649 A or C (CC) (CC)

 

[nandixon]

Thanks Anne! Can I ask what your result is for Yasko's SNP for SHMT1, i.e., rs1979277 ? It's possible people would need to have a defect in both MTHFS and SHMT in order to have an intolerance to folinic acid.

 

[anne_likes_red]

Thanks Anne! Can I ask what your result is for Yasko's SNP for SHMT1, i.e., rs1979277 ? It's possible people would need to have a defect in both MTHFS and SHMT in order to have an intolerance to folinic acid.

Sure. Sorry I missed that the first time. I'm GG. So no defect.
Anne.

 

[caledonia]

I haven't taken folinic acid, so don't know how I would react to it. But anyway, here are my results if you think it will help.

Edited to add 12-7-2013 - I don't know what I was thinking. Of course, there is folinic acid in the Thorne multi I took for many years. I don't have any problems with folinic acid.

SHMT1 GG

MTHFS, ST20-MTHFS 80136129 rs685487 A or G AG
MTHFS, ST20-MTHFS 80136288 rs8033649 A or C CC
MTHFS, ST20-MTHFS 80137560 rs8923 C or T TT
MTHFS, ST20-MTHFS 80138571 rs2733103 C or T CT
MTHFS, ST20-MTHFS 80138745 rs16971427 A or C AA
MTHFS, ST20-MTHFS 80141997 rs655473 A or G AA
MTHFS, ST20-MTHFS 80144197 rs17284990 C or T TT
MTHFS, ST20-MTHFS 80154571 rs16971450 A or G AA
MTHFS, ST20-MTHFS 80154982 rs6495446 C or T CC
MTHFS, ST20-MTHFS 80158042 rs7177659 A or C AC
MTHFS, ST20-MTHFS 80158159 rs6495449 A or G GG
MTHFS, ST20-MTHFS 80162265 rs17285431 A or C AA
MTHFS, ST20-MTHFS 80164053 rs6495451 C or T CC
MTHFS, ST20-MTHFS 80165368 rs2586154 A or G GG
MTHFS, ST20-MTHFS 80168282 rs12899781 G or T TT
MTHFS, ST20-MTHFS 80171971 rs16971478 A or G AA
MTHFS, ST20-MTHFS 80172133 rs2586153 C or T CT
MTHFS, ST20-MTHFS 80174388 rs2562744 A or C AA
MTHFS, ST20-MTHFS 80177687 rs2733106 A or G AG
MTHFS, ST20-MTHFS 80178283 rs12438477 A or C CC
MTHFS, ST20-MTHFS 80182050 rs12898642 C or T TT
MTHFS, ST20-MTHFS 80183766 rs2586182 A or C AA
MTHFS, ST20-MTHFS 80184657 rs2733088 A or G AA
MTHFS, ST20-MTHFS 80186340 rs12440798 C or T CC

 

[geesiddiqui]

MTHFS, ST20-MTHFS 80136129 rs685487 A or G AG
MTHFS, ST20-MTHFS 80136288 rs8033649 A or C CC
MTHFS, ST20-MTHFS 80137560 rs8923 C or T TT
MTHFS, ST20-MTHFS 80138571 rs2733103 C or T CT
MTHFS, ST20-MTHFS 80138745 rs16971427 A or C AA
MTHFS, ST20-MTHFS 80141997 rs655473 A or G AG
MTHFS, ST20-MTHFS 80144197 rs17284990 C or T TT
MTHFS, ST20-MTHFS 80154571 rs16971450 A or G AA
MTHFS, ST20-MTHFS 80154982 rs6495446 C or T CC
MTHFS, ST20-MTHFS 80158042 rs7177659 A or C AA
MTHFS, ST20-MTHFS 80158159 rs6495449 A or G GG
MTHFS, ST20-MTHFS 80162265 rs17285431 A or C AA
MTHFS, ST20-MTHFS 80164053 rs6495451 C or T CC
MTHFS, ST20-MTHFS 80165368 rs2586154 A or G AG
MTHFS, ST20-MTHFS 80168282 rs12899781 G or T TT
MTHFS, ST20-MTHFS 80171971 rs16971478 A or G AA
MTHFS, ST20-MTHFS 80172133 rs2586153 C or T CT
MTHFS, ST20-MTHFS 80174388 rs2562744 A or C AA
MTHFS, ST20-MTHFS 80177687 rs2733106 A or G AG
MTHFS, ST20-MTHFS 80178283 rs12438477 A or C CC
MTHFS, ST20-MTHFS 80182050 rs12898642 C or T TT
MTHFS, ST20-MTHFS 80183766 rs2586182 A or C AA
MTHFS, ST20-MTHFS 80184657 rs2733088 A or G AA
MTHFS, ST20-MTHFS 80186340 rs12440798 C or T CC

 

[nandixon]

This is adding everyone from the posts above and several posts that follow:

Rich=1, nandixon=2, Gestalt=3, Anne=4, caledonia=5, geesiddiqui=6, I.R.Baboon=7, Lynn_M=8

MTHFS 1 2 3 4 5 6 7 8
rs8923 CT (TT) (TT) (TT) (TT) (TT) (TT) (CT)
rs2733103 CC (CT) (CC) (CT) (CT) (CT) (CT) (CC)
rs16971427 AA (AA) (AA) (AA) (AA) (AA) (AA) (AA) x
rs655473 AA (AA) (AA) (AA) (AA) (AG) (AA) (AA)
rs17284990 TT (CT) (CT) (TT) (TT) (TT) (TT) (CT)
rs16971450 AA (AA) (AA) (AA) (AA) (AA) (AA) (AA) x
rs6495446 CT (CC) (CC) (CC) (CC) (CC) (CC) (CT) +++
rs7177659 CC (AA) (AA) (AA) (AC) (AA) (AC) (AA) ***
rs6495449 GG (GG) (GG) (AG) (GG) (GG) (GG) (GG)
rs17285431 AC (AA) (AA) (AC) (AA) (AA) (AC) (AA)
rs6495451 CT (CC) (CT) (CT) (CC) (CC) (CT) (CT)
rs2586154 GG (AG) (AG) (GG) (GG) (AG) (GG) (GG)
rs12899781 GT (TT) (TT) (GT) (TT) (TT) (GT) (TT)
rs16971478 AA (AA) (AA) (AA) (AA) (AA) (AA) (AA) x
rs2586153 CC (CT) (CC) (CT) (CT) (CT) (CC) (CC)
rs2562744 AA (AC) (CC) (AC) (AA) (AA) (AA) (AC)
rs2733106 AA (AG) (AA) (AG) (AG) (AG) (AA) (AA)
rs12438477 CC (CC) (AC) (AC) (CC) (CC) (CC) (AC)
rs12898642 CT (TT) (CT) (CT) (TT) (TT) (CT) (CT)
rs2586182 AA (AC) (AC) (AA) (AA) (AA) (AA) (AA)
rs2733088 AG (AG) (GG) (AG) (AA) (AA) (AG) (AG)
rs12440798 CC (CC) (CT) (CC) (CC) (CC) (CC) (CT)

My two additional MTHFS results (that Rich doesn't have):
2 4 5 6 7 8
rs685487 (GG) (AG) (AG) (AG) (AG) (AG)
rs8033649 (CC) (CC) (CC) (CC) (CC) (CC)

*** The AC variant of rs7177659 has less cardiovascular disease risk compared to AA and CC, therefore the homozygous states may increase/decrease enzyme activity (free full text not available: http://www.ncbi.nlm.nih.gov/pubmed/22649255/)
+++ Each T allele for rs6495446 reduces chronic kidney disease risk (http://www.biomedcentral.com/1471-2350/9/49/) This SNP is probably paired with rs8923.

 

[nandixon]

Thanks geesiddiqui, what is your SHMT1 result (rs1979277), and do you know if you have any problems with folinic acid? In the meantime I'll add your results to the post above.

 

[geesiddiqui]

Thanks geesiddiqui, what is your SHMT1 result (rs1979277), and do you know if you have any problems with folinic acid? In the meantime I'll add your results to the post above.

Hi! I'm GG for that, no known problems with folinic, though I haven't tried it consistently.

 

[I.R.Baboon]

Didn't notice any problems tolerating folinic acid.
Here are my results:

Gene, Position, SNP, Versions, Genotype
MTHFS, ST20-MTHFS 80136129 rs685487 A or G AG
MTHFS, ST20-MTHFS 80136288 rs8033649 A or C CC
MTHFS, ST20-MTHFS 80137560 rs8923 C or T TT
MTHFS, ST20-MTHFS 80138571 rs2733103 C or T CT
MTHFS, ST20-MTHFS 80138745 rs16971427 A or C AA
MTHFS, ST20-MTHFS 80141997 rs655473 A or G AA
MTHFS, ST20-MTHFS 80144197 rs17284990 C or T TT
MTHFS, ST20-MTHFS 80154571 rs16971450 A or G AA
MTHFS, ST20-MTHFS 80154982 rs6495446 C or T CC
MTHFS, ST20-MTHFS 80158042 rs7177659 A or C AC
MTHFS, ST20-MTHFS 80158159 rs6495449 A or G GG
MTHFS, ST20-MTHFS 80162265 rs17285431 A or C AC
MTHFS, ST20-MTHFS 80164053 rs6495451 C or T CT
MTHFS, ST20-MTHFS 80165368 rs2586154 A or G GG
MTHFS, ST20-MTHFS 80168282 rs12899781 G or T GT
MTHFS, ST20-MTHFS 80171971 rs16971478 A or G AA
MTHFS, ST20-MTHFS 80172133 rs2586153 C or T CC
MTHFS, ST20-MTHFS 80174388 rs2562744 A or C AA
MTHFS, ST20-MTHFS 80177687 rs2733106 A or G AA
MTHFS, ST20-MTHFS 80178283 rs12438477 A or C CC
MTHFS, ST20-MTHFS 80182050 rs12898642 C or T CT
MTHFS, ST20-MTHFS 80183766 rs2586182 A or C AA
MTHFS, ST20-MTHFS 80184657 rs2733088 A or G AG
MTHFS, ST20-MTHFS 80186340 rs12440798 C or T CC

//edit: SHMT1, rs1979277, AG

 

[nandixon]

Thanks I.R.Baboon, what is your result for SHMT1, i.e., rs1979277 ? Meantime I'll add your MTHFS results to post #13 above.

Edit: Never mind, I see from the thread you started that you're +/- (AG) for SHMT C1420T.

 

[Lynn_M]

Here are my results from 23andMe. I have not had Yasko testing so I don't know my SHMT. I took DMG Complete for 4 years, which includes 800 mcg folinic acid in its ingredients. I don't think I am intolerant to folinic acid. But I went through autonomic balancing testing 2 months ago, and because I muscle tested indifferent or negative to all my supplements and Rxs, I weaned down and then stopped all my supplements, including lifelong thyroid supplementation, mB12 and methylfolate. I was already gluten free, but also went dairy, egg, nightshade, corn, caffeine, and fermented food free for a clearing-out period. And I feel much better now, with much more energy, so maybe I had intolerances I didn't recognize. I don't have CFS, but previously I was always a low energy person. I am homo ++ for MTHFR A1298C, CBS A360A, and AA for 7177659.

I'm getting an error message posting with my genome results, saying I need to post less than 20 images, so I will try posting that part on a different post.

 

[I.R.Baboon]

Remove the little plus boxes (images) or copy/paste into notepad beforehand.

//edit: there also is an edit button

 

[Lynn_M]

I'm still getting the error message when I copy my results over, so here are my results in the order listed by 23andme for the MTHFS gene.
AG
CC
CT
CC
AA
AA
CT
AA
CT
AA
GG
AA
CT
GG
TT
AA
CC
AC
AA
AC
CT
AA
AG
CT
rs1979277 SHMT1 AG