Unfolded Protein Response and A Possible Treatment for CFS

[mariovitali]

@Valentijn

I will have to collect the relevant SNPs and formulate the hypothesis which i will do. In the meantime, you said :

All I know is that the SNPs being listed usually are not relevant.

What does "i know" refers to exactly and can you quantify it ? How about the word "usually"? Can you quantify that too for us?

How confident you are at what you said above? (In numbers of course!) How confident you are that a number of heterozygous SNPs ( say in Genes that are relevant to Choline) cannot lead to disease? Please point out the relevant Research of something similar. Notice the term "cannot"

I am all ears Valentijn

Needless to say that phrases like "i know" or "usually" is not scientific language. I am sure you know that... just saying for the others.

 

[Valentijn]

What does "i know" refers to exactly and can you quantify it ? How about the word "usually"? Can you quantify that too for us?

I honestly do not care. If you want to play make-believe and pick random SNPs to blame for random things, then have fun. It doesn't make it scientific or even sensible.

 

[mariovitali]

@Valentijn

Same mistake, over and over again...

From your last messages I am fairly certain that you do not fully understand what Randomness is and most importantly how it can be handled.

What is your major in, may I ask?

Please Educate yourself. I can point to you to relevant sources if you wish.


Luckily, the majority of Research Scientists do not think how you think. Otherwise there would have been no advances in Knowledge (I am sure that you do not understand why i said what i just said by the way)

Never Mind...all Good

 

[mariovitali]

The thread is working its way towards 1000 Conversations and i wanted to make a very quick summary.

1. Hypothesis : Apart from Methylation support, it may be beneficial for CFS Sufferers to take actions that aim to ameliorate ER and Oxidative Stress and to improve Redox homeostasis.

2. Several SNPs (e.g related to Choline, Riboflavin, Vitamin K, Thioredoxin, NOX4) may have to be considered and just providing Methylation support may not be enough in many cases : As an example, the interplay between Choline and Folate are well known for over 50 years [1]. Consider a case where an individual has a heterozygous MTHFR Mutation (which may impair Choline catabolism [1]) and also this individual has a homozygous MTHFD1 Mutation. The individual follows the Methylation protocol according to his gene SNPs.

Question : Should this individual supplement with Choline or not? Will the folate-dependent one-carbon transfer pathway work optimally or not after Folate supplementation to this individual? Please note that to my best of knowledge, Choline supplementation is not currently listed to any "Methylation Protocol"

3. Hypothesis : Chronic Fatigue, Post-Finasteride Syndrome and individuals suffering from Post-Accutane symptoms have the same basis : A stressor disrupts an already fragile environment when it comes to Redox Homeostasis and ER Stress handling. The result is a notorious cycle of Oxidative and ER Stress.

4. Hypothesis : Liver Function is a key aspect of CFS, PFS and Post-Accutane symptoms. Note that the relationship between Liver function and CFS/PFS/Accutane is not discussed on purpose.

5. Throughout the Thread i have made clear in several occasions that what is discussed are hypotheses. I am in no position to make ANY claims given my lack of knowledge and lack of data (among other things). I am not a medical professional and the reason behind creating this Thread was to generate interest from qualified practitioners about the validity of the hypotheses being discussed.

[1] Ed : Bailey, Folate in Health and Disease, Second Edition, 2010

 

[skwag]

Question : Should this individual supplement with Choline or not? Will the folate-dependent one-carbon transfer pathway work optimally or not after Folate supplementation to this individual? Please note that to my best of knowledge, Choline supplementation is not listed to any "Methylation Protocol"

Freddd's protocol does call for some choline.

Additional possibly helpful cofactors

Selenium
Lecithin
Chromium GTF
many other supplements

Like most things in the protocol it should be titrated to find the required dosage (easier said than done).

 

[mariovitali]

@skwag

Thank you for the correction

 

[skwag]

@mariovitali,

I have a feeling the answer to your question is that this individual needs to take choline ( or betaine ), which can also be used to spin the methionine-homcysteine wheel. But in order to justify this answer, we would need to know exactly what mutations the individual has, and how those mutations affect function.

In a healthy person, choline and folate are interchangeable in a way. If you have a lot of one, you don't need so much of the other.

Diet, Methyl Donors and DNA Methylation: Interactions between Dietary Folate, Methionine and Choline

DNA methylation influences the expression of some genes and depends upon the availability of methyl groups from S-adenosylmethionine (SAM). Dietary methyl groups derive from foods that contain methionine, one-carbon units and choline (or the choline metabolite betaine). Humans ingest ∼50 mmol of methyl groups per day; 60% of them are derived from choline. Transmethylation metabolic pathways closely interconnect choline, methionine, methyltetrahydrofolate (methyl-THF) and vitamins B-6 and B-12. The pathways intersect at the formation of methionine from homocysteine. Perturbing the metabolism of one of these pathways results in compensatory changes in the others. For example, methionine can be formed from homocysteine using methyl groups from methyl-THF, or using methyl groups from betaine that are derived from choline. Similarly, methyl-THF can be formed from one-carbon units derived from serine or from the methyl groups of choline via dimethylglycine, and choline can be synthesized de novo using methyl groups derived from methionine (via SAM). When animals and humans are deprived of choline, they use more methyl-THF to remethylate homocysteine in the liver and increase dietary folate requirements. Conversely, when they are deprived of folate, they use more methyl groups from choline, increasing the dietary requirement for choline. The availability of transgenic and knockout mice has made possible additional studies that demonstrate the interrelationship of these methyl sources. In summary, as we consider dietary requirements and possible effects on DNA methylation, it is important to realize that methionine, methyl-THF and choline can be fungible sources of methyl groups, and the design of our studies should reflect this.

So if something is seriously broken with the folate dependent pathway, the individual is going to need some choline.

 

[Valentijn]

First of all, thank you for putting forth an hypothesis which is easy to understand, especially for those of us who have not closely followed the discussion in this thread

2. Several SNPs (e.g related to Choline, Riboflavin, Vitamin K, Thioredoxin, NOX4) may have to be considered and just providing Methylation support may not be enough in many cases : As an example, the interplay between Choline and Folate are well known for over 50 years [1]. Consider a case where an individual has a heterozygous MTHFR Mutation (which may impair Choline catabolism [1]) and also this individual has a homozygous MTHFD1 Mutation. The individual follows the Methylation protocol according to his gene SNPs.

Regarding this part, I must agree with Skwag. It completely depends on which specific SNPs are involved, and what the research says about them (though scoring matrices and predictive algorithms can be applied to coding missense mutations). "A homozygous MTHFD1 mutation" isn't specific enough to reach any conclusions. Is there good-quality research showing that it has an impact? Is it a significant impact or a tiny impact? Which version has the impact? Does the research also indicate if the heterozygous genotype has an impact?

If there's no existing research for a SNP, then we run into different problems. Is it in a location where it has the potential to have an impact? Does a predictive algorithm or scoring matrix suggest that it could have an impact? How do we know if a rare variation is problematic or beneficial?

 

[Violeta]

Freddd's protocol does call for some choline.



Like most things in the protocol it should be titrated to find the required dosage (easier said than done).

In that passage, Fredd said chromium, not choline.

But Chris Masterjohn says choline is the answer to fatty liver AND methylation.

Folate may be some sort of fix for methylation, at least for some people, but it doesn't fix fatty liver.
Choline fixes the problem. Read through the methylation forum and you'll see people coming up with Parkinsonian symptoms from trying to force methylation correction with folate.

http://blog.cholesterol-and-health.com/2010/11/does-choline-deficiency-contribute-to.html

Does Choline Deficiency Contribute to Fatty Liver in Humans

 

[mariovitali]

@skwag

I also agree with you. Choline could be supplemented in this case

@skwag, @Valentijn

Try to extend what i discussed about Choline with another example. Consider the following two individuals :

1. MTHFR (+/+), rs561712(-/-), rs1879417(-/-),rs7977109(-/-) (rs##### = NOS1)

and

2. MTHFR(-,-),rs561712(+/+), rs1879417(+/+),rs7977109(+/+)


And now the Questions (assuming there are no other genes involved):

-Which individual is more likely to have problems with Nitric Oxide production? None? One of them or Both of them?
-Now add to the Equation another 100 genes related to NOS1. Would that change the outcome? If yes, How and how confident we are? (Make a note on how this addition of Genes may potentially alter things)

What i am trying to say is that this is a problem with many-many-many-many factors.


So my *hypothesis* is that if we do not look at an expanded way different SNPs, we are getting nowhere.


@Valentijn

First of all, Thank you for having a more productive attitude, much appreciated.


You say :

"A homozygous MTHFD1 mutation" isn't specific enough to reach any conclusions. Is there good-quality research showing that it has an impact? Is it a significant impact or a tiny impact? Which version has the impact? Does the research also indicate if the heterozygous genotype has an impact?

Before continuing : MTHFD1 does have a specific impact and the next thing is to state which impact. So yes it does have an impact according to Research, namely to Choline metabolism. If we agree on that, we can move on.

So Let's move on to :

If there's no existing research for a SNP, then we run into different problems. Is it in a location where it has the potential to have an impact? Does a predictive algorithm or scoring matrix suggest that it could have an impact? How do we know if a rare variation is problematic or beneficial?

Because of the multifactorial nature of the problem (CFS) it is very hard to make Research. Consider the relevant Genes, their SNPs and as a consequence their combinations. Now add Nutrient status, age, sex, location, diseases experienced...

Given the fact that this is a very hard problem, this does not mean that we cannot make some hypotheses which we may wish to try on not try. If i would wait as a prerequisite for Research to catch up in order to do something for my deteriorating Health i don't know where i would be now @Valentijn. I hope this makes sense. You also have no idea how much emotionally charged i felt as i was writing this (in red letters) because no one but myself knows what i've been through (Please visit the first page of the Thread and re-read the number of Symptoms that i had). I am sure the same applies for all you.


@Valentijn Why don't you try what is suggested here. You have your DNA Data. Even though there is no research for many genes discussed here just go ahead and give it a try : Do you have SNPs on Thioredoxin functioning? Take some selenium. Do you have some SNPs to Vitamin K metabolism? Take some Vitamin K. Do this DESPITE the lack of evidence. Evaluate how you feel after a month.

I would be the most positive advocate of your way of thinking in one case : If we were confident that we know *everything* and researched *everything* about the human body.

It's SO simple!

 

[Violeta]

Just a heads up about Vitamin K, @mariovitali, most people need to take the K2 form. If your body doesn't convert K to K2 the K can make your blood coagulate. K2 corrects calcium dysregulation. If you want extra K1 just eat a lot of kale or cauliflower, see how you feel.

 

[mariovitali]

Just a heads up about Vitamin K, @mariovitali, most people need to take the K2 form. If your body doesn't convert K to K2 the K can make your blood coagulate. K2 corrects calcium dysregulation. If you want extra K1 just eat a lot of kale or cauliflower, see how you feel.

My theory is that in our case, Vitamin K has a more profound role because of its Redox potential.

 

[Gondwanaland]

Vitamin K has a more profound role because of its Redox potential.

Could you please expand on that a little? I don't get it
My dr. said excess K2 can be reconverted to K1 - and I think I run into that. Right now I am optimizing my thyroid hormone intake and hope this will help me to tolerate K2 without inflammation. Ideally my liver should be able to convert from K1, but AFAIK it hasn't been optimal for a long time.

 

[Valentijn]

Before continuing : MTHFD1 does have a specific impact and the next thing is to state which impact. So yes it does have an impact according to Research, namely to Choline metabolism. If we agree on that, we can move on.

Of course the gene has an impact. But most of the SNPs on it do not impact the functioning of the gene. So it cannot be said that because rs0000000 is on geneXYZ, rs00000000 will cause geneXYZ to function differently. And even if it is likely to make geneXYZ function differently, there really is no good way to know if the altered functionality is beneficial or harmful, or if the impact is moderate or insignificant.

Because of the multifactorial nature of the problem (CFS) it is very hard to make Research.

The research of SNPs absolutely does not need to involve ME/CFS. Any research into SNPs is likely to be relevant to gene functioning, regardless of the illness involved. The gene (typically) causes some process into the body to happen slower/less or faster/more. If SNPs are causing that alteration, it will be present regardless of the illness. If it's the illness itself causing the alteration, then the SNPs aren't really relevant anyhow.

Given the fact that this is a very hard problem, this does not mean that we cannot make some hypotheses which we may wish to try on not try.

There's a difference between proposing or exploring a hypothesis, versus encouraging a treatment based on that hypothesis. And if the hypothesis is that normally functioning SNPs are causing problems, there is probably a basic flaw with that hypothesis.

@Valentijn Why don't you try what is suggested here. You have your DNA Data. Even though there is no research for many genes discussed here just go ahead and give it a try : Do you have SNPs on Thioredoxin functioning? Take some selenium. Do you have some SNPs to Vitamin K metabolism? Take some Vitamin K. Do this DESPITE the lack of evidence. Evaluate how you feel after a month.

I'm not trying it because a hypothesis involving SNPs which are mostly either known not to have an impact, or lacking any research into them, isn't a reasonable basis to go out and buy a lot of supplements and swallow more pills every day.

And what do you mean "have SNPs?" Everyone has SNPs. Over 3 billion of them, in fact. Which ones are important? The thousands on each of those genes? Just the handful 23andMe tests for? Only the ones where you have a variation that isn't extremely common? Everyone, healthy or otherwise, has thousands of rare SNPs. It doesn't mean anything significant to have a few on genes which you find of interest. Because you and everyone else have them on most of your other genes as well.

I would be the most positive advocate of your way of thinking in one case : If we were confident that we know *everything* and researched *everything* about the human body.

Lack of sufficient scientific research into SNPs is not an excuse to start guessing at random. It just means we need more proper research.

 

[Violeta]

My theory is that in our case, Vitamin K has a more profound role because of its Redox potential.

Try it, see how you do.

 

[mariovitali]

@Valentijn

I do not have anything else to say, apart from the fact that both our opinions are documented in this site.

In the *unlikely* event that whatever is discussed in this Thread does lead to significant increase of Quality of life -say for 60 out of 80 people who have tried it- would you try it?

 

[mariovitali]

Could you please expand on that a little? I don't get it
My dr. said excess K2 can be reconverted to K1 - and I think I run into that. Right now I am optimizing my thyroid hormone intake and hope this will help me to tolerate K2 without inflammation. Ideally my liver should be able to convert from K1, but AFAIK it hasn't been optimal for a long time.

See this post :

Unfolded Protein Response and A Possible Treatment for CFS

 

[Gondwanaland]

Consider the relevant Genes, their SNPs and as a consequence their combinations. Now add Nutrient status, age, sex, location, diseases experienced...

+ medicines taken

In my experience, my health decline had a heavy involvement of medicines taken. But why did my husband and I need meds? Bad dietary choices (?). Why the food we ate did us so much harm, while other people eating the same stuff or worse thrived? Because other people have better redox responses due to genetic differences, or lifestyle, or mindset, or something they eat and we don't (I have always wondered about the fact that the ones in my husband's family who eat garlic are disease free - is that just a silly detail or does it involve the dissulfide bonds?)

When my husband needed choline he has been prescribed acetaminophen
When I needed a gluten free diet I have been prescribed accutane, heparin, warfarin
I will never know if we already had NAFLD when we started the meds, but it doesn't matter because the meds either created or aggravated it.

I don't think that I would have ever realized that we didn't have enough choline in our diets if it wasn't for you, Mario.

And that link posted by @Violeta to Masterjohn's blog about choline is extremely elucidative I am so glad we can get away with choline only and don't need folate. Folate has too many side effects.

http://blog.cholesterol-and-health.com/2010/11/does-choline-deficiency-contribute-to.html

Does Choline Deficiency Contribute to Fatty Liver in Humans

 

[skwag]

Freddd's protocol does call for some choline.

In that passage, Fredd said chromium, not choline.

I was referring to lecithin, which many use to supplement choline. Freddd also suggests TMG, or betaine, may be required.

Folate may be some sort of fix for methylation, at least for some people, but it doesn't fix fatty liver.
Choline fixes the problem. Read through the methylation forum and you'll see people coming up with Parkinsonian symptoms from trying to force methylation correction with folate.

Agreed on the need for choline to fix fatty liver. The "Parkinsonian symptoms" is an interesting observation. What symptoms exactly are you refering to?

 

[Violeta]

I was referring to lecithin, which many use to supplement choline. Freddd also suggests TMG, or betaine, may be required.



Agreed on the need for choline to fix fatty liver. The "Parkinsonian symptoms" is an interesting observation. What symptoms exactly are you refering to?

Yes, you're right, @skwag , my mistake.

I don't know what the exact symptoms were that they were referring to. It was being discussed in the methylation forum, which I had been following until I read the B2 I Love You thread, and started working on it a different way. You might be able to go back to that by doing a search on Parkinsonian. Some people didn't use that word, just said they were having problems. No one knew why, but someone did find a page on Ben Lynch's site where he said that people with "certain" health issues have to work things out differently. I don't even know if Ben Lynch said what those certain health issues are, and he should make that information more widely known, but that's not happening.