Help me with my 23andme results

[pogoman]

In the case of MTHFR there's a lot of solid research into the missense mutations which cause reduced enzyme activity. While many SNPs (especially non-coding ones) on many genes are prone to having vague, contradictory, and low-quality support for their impact, that is not always the case.

It's been found pretty consistently that MTHFR C677T (rs1801133), for example, results in 70% reduction in enzyme activity when homozygous, and about 35% reduction in enzyme activity when heterozygous. Numerous studies consistently associate this with a modest elevation in various health risks: elevated homocysteine, and various folate-related birth defects when the mother has a mutation.

Things can and do get a bit crazy at that point, and some people then engage in various histrionics about their "broken" genes and the need to spend a lot of money on low-dose Yasko supplements which ironically don't even take into account the reduced ability to convert inactive (and cheap) folic acid into an active (and expensive) form. But again we can go back to the research, and find a couple of papers which show that people with these mutations completely remove the elevated risk factor if they supplement with an active folate or simply eat a respectable amount of vegetables as part of their regular diet.

The other common source of passionate misunderstandings is that people assume that having one of these mutations is exactly equivalent to having a disease, and that they are "diagnosed with having MTHFR" or similar. But if we look at prevalence rates of these mutations, it's obvious that they're far more common than any disease (or all diseases), and people usually live with them with little or no problem. On average, people have a 30-40% reduction in MTHFR gene function compared to optimal function. Hence it's nothing to get excited about when someone joins the 10% of the population with MTHFR C677T +/+. Just take a supplement or eat some damned vegetables, especially during pregnancy. Problem solved.

theres one thing you didn't mention that I believe is a big factor with mthfr (and probably others)- aging and its effect on whatever bad SNPs they may have.

both my sister and myself starting having really bad issues when she was in late 40s and I was in my early 50s.
but looking back I can see periods of my life that probably were complicated by mthfr.
hypergonadism, anemia, thyroid at bottom of normal for the past two decades and doctors unable to explain.
all progressively worse as I got older and increased by exercise and physical activity.
I must have spent a thousand or two on supplements without getting anywhere, not until I found out that supporting with mitochondrial and methylation factors made a big difference.

for what its worth, my sister takes Metanx once a day since she found out and does well on it.

also one other thing re mthfr.
high homocysteine levels are not always a reliable marker for mthfr issues.
I'm the exception that proves the rule, normal homocysteine when they checked a few years ago, which all the doctors have used to say mthfr is not an issue with me.

 

[Jonathan Edwards]

Thanks for the very useful points, Valentijn. That makes me a little less ignorant - and I am very ready to admit my ignorance is still substantial.

Maybe of all the points made so far the sentence in the review cited by pogoman highlights my concerns:

'Recent evidence suggests that high levels of methyl donor intake may also have detrimental effects.'

The topic of the review is 'Is more always better?'.

If these alleles are so common that 10% are homozygous it seems likely that either they do not matter much to health (which judging from the data available is probably not the right answer) or they confer both disadvantages and advantages in different situations. High homocysteine may be just the ticket under certain circumstances. If the allele was all bad then it ought to have died out, or at least never become common.

It looks to me as if we are about at the stage we were with cholesterol about thirty years ago before people understood about LDL andHDL and all that. We have had so many of these health advice issues that have gone around in circles. So far my impression is that other than making sure pregnant women have enough folate in general (the mechanism of benefit not being known) and that people do not have pernicious anaemia it is very unclear that any advice should be given to people about supplementation on the basis of these gene polymorphisms.

And since having been directed to some of the evidence it looks as if we are looking at things like risk of cancer then this looks to me to fall fairly squarely into the realm of 'medical advice', just as much as whether or not to take HRT or the pill might be in the context of thromboembolism and breast cancer. So if anything I feel more convinced that PR is not the place for recommending supplement protocols to others, especially when very often we do not even know what their health issues are!

 

[Valentijn]

If these alleles are so common that 10% are homozygous it seems likely that either they do not matter much to health (which judging from the data available is probably not the right answer) or they confer both disadvantages and advantages in different situations.

With some of the more common significant missense mutations, I think it might be a matter of the gene function being largely irrelevant if eating appropriately. The common MTHFR mutations become completely irrelevant if someone is not relying upon forms of folic acid which need to be converted to become an active form, for example. Hence a diet high in the right vegetables would make the gene pretty irrelevant, but that situation might change if someone starts subsisting on Ritz crackers.

Similarly, MTRR is involved in basically recycling the B12 used by another gene. This might be very important if eating little meat or on a vegetarian diet, but not such a big deal if someone's embracing their inner carnivore.

I'd be very interested to know if these sorts of mutations predispose people to favor or avoid certain diets. In my own case, I'm generally not fond of vegetables, especially leafy greens, though don't have any MTHFR defects so I can probably get away with avoiding veggies more than some people. And I do have a fairly big reduction in MTRR function (enzyme function at about 30%), so perhaps that influences my love of meat and helps in explaining why I feel awful if I go more than 12 hours without eating something that used to be cute and fuzzy.

But that's a lot of unsubstantiated pondering, and not something I'd base supplement advice upon

 

[Gondwanaland]

If the allele was all bad then it ought to have died out, or at least never become common.

AFAIK the induvidual must die before reproductive age in order to the gene die out.

Hence a diet high in the right vegetables would make the gene pretty irrelevant

Easier said than done, some people have MCS, which includes plants.

 

[Jonathan Edwards]

AFAIK the induvidual must die before reproductive age in order to the gene die out.

I think you just have to be ill enough to be less attractive to the opposite sex, or less good at gathering food or defending the children against predators, or even less good at helping with food production and child care as a grandparent. If your kids do not survive nor do your genes.

 

[Gondwanaland]

I think you just have to be ill enough to be less attractive to the opposite sex, or less good at gathering food or defending the children against predators, or even less good at helping with food production and child care as a grandparent. If your kids do not survive nor do your genes.

Why don't they all disappear the genetic disavantages leading to disease? Or have they already?

 

[Jonathan Edwards]

Why don't they all disappear the genetic disavantages leading to disease? Or have they already?

Presumably because the genes also convey advantages. The classic cases are Glucose 6 phosphate dehydrogenase deficiency and sickle cell trait if I remember rightly. They protect you from infection but at the risk of haemolytic anaemia. That is the key point. A gene variant may be bad in one situation and good in another.

 

[ahmo]

Heavens above, Rich VanK spent years here developing methylation protocols. He called it Simple Methylation Protocol because he was designing something to be used by people who hadn't had genetic testing. But there was certainly an aknowledgement of the centrality of methylation problems for many of us in the ME cohort.

 

[Jonathan Edwards]

Heavens above, Rich VanK spent years here developing methylation protocols. He called it Simple Methylation Protocol because he was designing something to be used by people who hadn't had genetic testing. But there was certainly an aknowledgement of the centrality of methylation problems for many of us in the ME cohort.

But I still would like to know why anybody thought that?

 

[ahmo]

But I still would like to know why anybody thought th

Sorry, I don't have the historical information, nor the ability to formulate an argument. It's one of the areas, maybe the, or the most significant, area where we have similarities w/ autism. But the fact is, many of us have experienced significant benefits, that's not a thought, but a reality.

 

[Jonathan Edwards]

Sorry, I don't have the historical information, nor the ability to formulate an argument. It's one of the areas, maybe the, or the most significant, area where we have similarities w/ autism. But the fact is, many of us have experienced significant benefits, that's not a thought, but a reality.

Is there a relation between autism and methylation? It looks as if there may be some abnormally methylated genes in autism but that is quite different from an abnormality of methylation per se.

 

[Hip]

After I found out thru 23and me I was homozygous for MTHFR, I had a senior genetic doctor at Kaiser tell me that MTHFR was not the cause of my myopathy and fatigue
Yet 6 months later, after analyzing my 23andme results and learning from members here, I am almost pain free.

Are you saying that you started Rich Van K's standard simplified methylation protocol and you felt better as a consequence?

Or are you saying that you got better by analyzing your 23andme results and tweaking your supplement regimen according to those 23andme results?

If the latter, what tweaks did you make?

 

[Hip]

I wonder if it is worth setting up a poll to establish if there is a connection between a ME/CFS patient's 23andme results (and in particular their methylation-associated SNPs), and whether or not they benefit from the simplified methylation protocol.

An existing Phoenix Rising poll on methylation found that around 25% of ME/CFS patients report major benefits from the simplified methylation protocol.

Might it be that patients who get major benefits from methylation have certain SNPs that make them undermethylators? And might it be that patients who don't benefit from methylation have certain SNPs that make them overmethylators?

If such a poll showed that the ME/CFS patients who get major benefits from methylation are those who more frequently have certain SNPs that make them undermethylators, then this would accomplish three useful things:

• It would perhaps tend to support the idea that your methylation status is linked to your SNPs.
• It would add weight to the theory that methylation can be beneficial for a subset of ME/CFS patients.
• It would become a useful tool in the future for determining, on the basis of their 23andme results, which new ME/CFS patients will most likely benefit from methylation.



The only issue is that the data which needs to be analyzed may be a little too complex to be accommodated in a basic PR poll.

Though it might still be worth doing a basic PR poll, even just as a first attempt. The poll would be open only to ME/CFS patients who observed a major improvement from methylation, and the poll would simply ask patients to select the methylation SNPs that they are homozygous (+/+) for, with the poll listing all the 26 SNPs that relate to methylation, from the Genetic Genie report.



But ideally we would need to work out beforehand the SNPs that make someone an overmethylator, and the SNPs that make someone an undermethylator. Then on the basis of each person's SNPs, they could be scored on their theoretical ability to methylate. Though I have not seen any quantitative stuff like this from Amy Yasko which could produce a numerical theoretical ability to methylate score from a person's SNPs.

But assuming such a scoring system were available, we could then check whether it is indeed the undermethylators who get the most improvements in their ME/CFS from doing the methylation protocol.

 

[ahmo]

Is there a relation between autism and methylation? It looks as if there may be some abnormally methylated genes in autism but that is quite different from an abnormality of methylation per se.

There are a number of similarities, overlapping symptoms, including gut and neurological. Some of the same strategies, including diet and methylation supps work in both groups.

@Hip Here's a thread which includes contributions of both Rich and Fred re over/under methylation. I've linked Fred's post re why those terms are not necessarily helpful.

Also, re a poll about SMP: for me, Rich's SMP did not work. But Freddd's Protocol has been magnificent. So if you create a poll, please either differentiate those 2, or just ask re methylation, without specifying. And, as has often been noted here, it's likely that some who've benefited from methylation have gone on to other lives, away from pr.

http://forums.phoenixrising.me/inde...ursers-laymans-version.1740/page-2#post-46262
I have taken that list of under and over methylators (sounds like some kind of rifle-shotgun combo) symptoms and categorized them as to type of b12 deficiency(s) by color and grouping them based on what symptoms I used to have....

 

[Hip]

@ahmo
Point taken about including all variations on the methylation protocol.

The idea of this poll is to see if there is any evidence that methylation-related gene SNPs play a role in which ME/CFS patients benefit from the methylation protocol.

 

[pogoman]

Are you saying that you started Rich Van K's standard simplified methylation protocol and you felt better as a consequence?

Or are you saying that you got better by analyzing your 23andme results and tweaking your supplement regimen according to those 23andme results?

If the latter, what tweaks did you make?

Not Rich, but actually freddd.
I looked up when I found out my sister had mthfr, it was actually two years ago and while googling info, it was freddd's posts that I ran across about methyl B12 and methyl folate.
I used his info he posted back then to take the recommended supplements along with P5P and glutathione, while there was some transient improvement my myopathy continued to get worse and my CPK numbers continued to climb.

I had taken a bunch of labs last year from various specialists and to me they indicated my issues were symptoms and not causes.
I had no inflammation so that eliminated auto immune diseases and I was left with just a genetic cause as a possibility.
so I started taking various supplements to see what helped, while I had tried them previously I had not taken them together.
I found riboflavin B2 and coq10 taken together helped reduce symptoms almost immediately.
I was able to reduce taking opiates after a couple months.
researching on that, I came to the conclusion I had some kind of mitochondrial or metabolic disorder.

I found carnitine and choline together helped also, by then I also had my 23andme results verifying I also had mthfr.
so along with the above, I started on the same methylation program again with methyl B12 and methyfolate and switched to LCF instead of acetyl carnitine after reading posts about it.

I also tried various supplements I read about here that fit my SNPs, the one that really helped was lithium orotate.
as I found out afterwards I am +/+ for the TCN2 C776G mutation that slows B12 transit into the cells, that explains why it helps me.
I also take once a week or so phosphorus and manganese, which are mitochondrial cofactors.
at the present time, I am taking alot of methyl B12, I am guessing around 20mg total thru out the day.

here is what the genetic doctor emailed me after I let him know about my 23andme results.

It doesn't matter what your MTHFR genotype is: your plasma homocysteine was measured (the amino acid which mediates MTHFR effect) and was completely normal. There is no additional testing suggested.

Unfortunately, we cannot use the 23andme info for clinical decision making; we would need to log onto the site with you in order to get a level of information to interpret. However , as I stated, this is moot with respect to MTHFR and EFTHD.

 

[adreno]

But I still would like to know why anybody thought that?

Rich's main idea was that the increased oxidative stress often hypothesized in ME (Pall et al) is caused by low intracellular glutathione.

He explained how the pathophysiology of ME could lead to a functional deficiency of (in particular) B12, leading to a hypoactive methylation cycle, in turn causing low glutathione.

I think his hypothesis was sound, but never proven. Please see his paper for a better understanding. It also discusses similarities between ME and autism. At least look at the theory before you dismiss it. Rich's hypothesis is an important part of PR history.

http://phoenixrising.me/research-2/...ue-syndrome-by-richard-a-van-konynenbury-ph-d

 

[Valentijn]

Is there a relation between autism and methylation? It looks as if there may be some abnormally methylated genes in autism but that is quite different from an abnormality of methylation per se.

There is according to Yasko They're her primary target for selling supplements.

 

[Valentijn]

An existing Phoenix Rising poll on methylation found that around 25% of ME/CFS patients report major benefits from the simplified methylation protocol.

That's not a poll of ME/CFS patients - it's a poll of forum users. And that particular subforum has a HUGE number of non-ME/CFS patients who come to discuss methylation.

 

[Sea]

Though it might still be worth doing a basic PR poll, even just as a first attempt. The poll would be open only to ME/CFS patients who observed a major improvement from methylation, and the poll would simply ask patients to select the methylation SNPs that they are homozygous (+/+) for, with the poll listing all the 26 SNPs that relate to methylation, from the Genetic Genie report.

One of the problems is that there are hundreds (or maybe more) of snps that relate to methylation, not just the 26 on GG which came from Yasko.