Poll: rs11627387 MTHFD1

[Kimsie]

rs12939757 (edit: this is supposed to say rs11627387) is a loss of function variant of MTHFD1 which is fairly common with AA (the risk allele) being about 12% on OpenSNP. I think this allele may be significant only when a person is experiencing oxidative stress.

 

[Valentijn]

rs12939757 is a loss of function variant of MTHFD1 which is fairly common with AA (the risk allele) being about 12% on OpenSNP. I think this allele may be significant only when a person is experiencing oxidative stress.

I think you've listed the wrong SNP here, since rs12939757 isn't on the MTHFD1 gene.

What do you mean by "loss of function"? Why do you believe that rs11627387 is having a significant impact? What's the basis for suggesting that oxidative stress specifically interacts with this non-coding SNP?

 

[Kimsie]

I think you've listed the wrong SNP here, since rs12939757 isn't on the MTHFD1 gene.

Yes, I had the wrong SNP in at first and I missed getting it changed in that one spot. It's supposed to be rs11627387. Sorry about that.

What do you mean by "loss of function"? Why do you believe that rs11627387 is having a significant impact? What's the basis for suggesting that oxidative stress specifically interacts with this non-coding SNP?

This study found that it is associated with increased risk for heart defects (at least in hispanic women). I take this to be evidence that it is a loss of function change although perhaps that is slim evidence. I am planning to talk about my reasons for believing that it might be significant soon in another post to start a new thread because it is pretty complicated, but basically loss of function in MTHFD1 has been found to cause problems with thymidylate synthesis and methionine recycling (in a real person, not in a rat or mouse). Since MTHFD1 requires NADPH to go in the direction of 5,10-methyleneTHF, which is needed for thymidlylate and methionine synthesis, it seems logical to me that oxidative stress, which will drain NADPH, could increase the negative effects of loss of function mutations in MTHFD1. This SNP is only one of the possible SNP's involved. I would imagine that a person could have more than one SNP affecting the pathway, and that multiple SNP's would increase the effect.

I am particularly interested in this SNP because my son with depression is AA for this SNP and I suspect that my son with schizophrenia is AA, too, because our 3rd son is AA, (our daughter is AG, and I am AG, but I suspect that my husband is AA.) I believe that my sons' problems are caused by loss of function SNP's in the MTHFD1 pathway, and this is the only one that I can find that they have homozygous mutations on, so far, for which I have evidence of loss of function. I am planning to explain about this in the other post when I can get it together.

 

[Valentijn]

This study found that it is associated with increased risk for heart defects (at least in hispanic women). I take this to be evidence that it is a loss of function change although perhaps that is slim evidence.

That SNP has a very small effect size (slightly increased risk of cardiac birth defects), which would indicate the impact of it is relatively mild. It is extremely unlikely that it results in loss of gene function, especially since it has not been marked as pathogenic.

 

[Kimsie]

That SNP has a very small effect size (slightly increased risk of cardiac birth defects), which would indicate the impact of it is relatively mild. It is extremely unlikely that it results in loss of gene function, especially since it has not been marked as pathogenic.

Yes, by itself it wouldn't be significant, but in combination with other MTHFD1 mutations and with oxidative stress, it might add to the negative effect. Since it might only be significant in combination or with certain stress conditions, it would be less likely to be spotted as a loss of function mutation.

If you happen to have a list of MTHFD1 loss of function mutations with their rs numbers, I would be interested in the information. It might be better to look at the combination of these mutations rather than one mutation. Maybe a poll of all of these mutations would be more informative.

 

[Kimsie]

That SNP has a very small effect size (slightly increased risk of cardiac birth defects), which would indicate the impact of it is relatively mild. It is extremely unlikely that it results in loss of gene function, especially since it has not been marked as pathogenic.

Also, why do you think that it does not result in any loss of function? What other reason could there be for it to have any impact on birth defects?

 

[mariovitali]

@Kimsie

MTHFD1 may be important for Choline absorption so i suggest you look into it.

In one study, a common genetic polymorphism, 5,10 methylenetetrahydrofolate dehydrogenase1958A (MTHFDI), in folate metabolism made premenopausal women 15 times more likely to develop signs of choline deficiency on a low-choline diet as non-carriers of the SNP (p < 0.0001). The impact of this SNP is quite large - 63% of the study population had at least one allele with the SNP. The MTHFD1 allele is believed to change the flux between 5,10-methylenetetrahydrofolate and 10-formyltetrahydrofolate, which influences the availability of 5-methyltetrahydrofolate for homocysteine methylation (and subsequent methionine and then SAM production). This would mean more choline would be shunted towards methylation to make up for the lack of folate participation in the pathway.[58] A real-world application of this is the risk of having a child with a neural-tube defect is increased in mothers with the G1958A SNP in MTHFD1.[77] Additionally, mice that are Mthfr -/- (lacking MTHFR) become choline deficient, suggesting that humans with genetic polymorphisms that alter the functionality of the enzyme may also have choline deficiency problems.

https://en.wikipedia.org/wiki/Choline

 

[Valentijn]

Also, why do you think that it does not result in any loss of function? What other reason could there be for it to have any impact on birth defects?

I misunderstood what you meant by "loss of function". It can cover a huge range of impact, from making the gene completely nonfunctional to an insignificant down-regulation. I think I'd describe this one as being a mild down-regulation, for clarity.

That the SNP only attains significance in a sub-sample is also a red flag. If the SNP in isolation has an impact in one human, it should have a similar impact in other humans. A couple things could be happening, other than actual significance solely in Hispanics. One possibility is that it's just a false positive, which happens a lot in SNP research of this type. Another possibility is that the SNP is in varying degrees of linkage disequilibrium in different ethnicities, and is merely reflecting the increased prevalence of the actually relevant SNP in one of those groups.

I'd consider this study to provide weak evidence of a minor impact. It needs to be replicated to confirm any correlation, and it would be nice to see actual folate levels measured as well, which would provide much stronger and more direct evidence of a down-regulation.

 

[ahmo]

Lecithin + citicoline + Alpha GPC choline have helped my oxidative stress symptoms. Also, re choline:

http://www.ncbi.nlm.nih.gov/pubmed/21270363# 2011 Mar;141(3):531-4. doi: 10.3945/jn.110.130369. Epub 2011 Jan 26.

Nutritional genomics: defining the dietary requirement and effects of choline.

http://www.ncbi.nlm.nih.gov/pubmed/?term=Zeisel SH[Author]&cauthor=true&cauthor_uid=212703631.

http://www.ncbi.nlm.nih.gov/pubmed/21270363#


Abstract

As it becomes evident that single nucleotide polymorphisms (SNPs) in humans can create metabolic inefficiencies, it is reasonable to ask if such SNPs influence dietary requirements. Epidemiologic studies that examine SNPs relative to risks for diseases are common, but there are few examples of clinically sized nutrition studies that examine how SNPs influence metabolism. Studies on how SNPs influence the dietary requirement for choline provide a model for how we might begin examining the effects of SNPs on nutritional phenotypes using clinically sized studies (clinical nutrigenomics). Most men and postmenopausal women develop liver or muscle dysfunction when deprived of dietary choline. More than one-half of premenopausal women may be resistant to choline deficiency-induced organ dysfunction, because estrogen induces the gene [phosphatidylethanolamine-N-methyltransferase (PEMT)] that catalyzes endogenous synthesis of phosphatidylcholine, which can subsequently yield choline. Those premenopausal women that do require a dietary source of choline have a SNP in PEMT, making them unresponsive to estrogen induction of PEMT. It is important to recognize differences in dietary requirements for choline in women, because during pregnancy, maternal dietary choline modulates fetal brain development in rodent models. Because choline metabolism and folate metabolism intersect at the methylation of homocysteine, manipulations that limit folate availability also increase the use of choline as a methyl donor. People with a SNPs in MTHFD1 (a gene of folate metabolism that controls the use of folate as a methyl donor) are more likely to develop organ dysfunction when deprived of choline; their dietary requirement is increased because of increased need for choline as a methyl donor.

 

[Kimsie]

Lecithin + citicoline + Alpha GPC choline have helped my oxidative stress symptoms. Also, re choline:

Choline can be changed into betaine and recycle methionine through BHMT but taking a methionine supplement should help avoid draining choline, unless the person has a problem in the transsulferation pathway.

 

[Kimsie]

I misunderstood what you meant by "loss of function". It can cover a huge range of impact, from making the gene completely nonfunctional to an insignificant down-regulation. I think I'd describe this one as being a mild down-regulation, for clarity.

That the SNP only attains significance in a sub-sample is also a red flag. If the SNP in isolation has an impact in one human, it should have a similar impact in other humans. A couple things could be happening, other than actual significance solely in Hispanics. One possibility is that it's just a false positive, which happens a lot in SNP research of this type. Another possibility is that the SNP is in varying degrees of linkage disequilibrium in different ethnicities, and is merely reflecting the increased prevalence of the actually relevant SNP in one of those groups.

I'd consider this study to provide weak evidence of a minor impact. It needs to be replicated to confirm any correlation, and it would be nice to see actual folate levels measured as well, which would provide much stronger and more direct evidence of a down-regulation.

I agree that the study is not very strong evidence, but it is some evidence that this SNP produces a mild down-regulation. But I disagree with your apparent assumption that a mild down-regulation is insignificant. I think for some people it can be the straw that breaks the camel's back when there are other "insignificant" factors added to it.

 

[aquariusgirl]

GG here ....

 

[Kimsie]

Here is another study where rs11627387 was found to be involved in the probability of birth defects, in this case TD defects. So far I haven't found any other studies with this SNP. In this study the risk was only increased when folate intake was low. I feel this is actually significant, because what I am looking for are SNP's that could cause the body to compensate by localizing MTHFD1 to the nucleus, at least under conditions of oxidative stress. I am not looking for SNP's that cause actual damage in and of themselves. It is the localization of MTHFD1 in the nucleus which causes undermethylation of the histones, according to my hypothesis, which I hope to post about soon.

I have no way of knowing whether CFS/ME is affected by undermethylation or not. And this SNP is only one of several that could be involved it it was so. But if it is so, I do think it could be something affecting people who have problems with refeeding, since the thymidlyate pathway is involved.