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Summarise further report pros and cons after 23andme?

alicec

Senior Member
Messages
1,572
Location
Australia
Not sure why you are getting so defensive

No, not defensive in the slightest. I was simply astounded by what you seemed to be saying.

I am a tolerant and patient person and try to understand the point of view of others but your statements were just too much for me. I was expressing my astonishment.

Adding the qualification that a bad environment as well as degree of sickness might influence "expression of a SNP" (to use your terminology, but one I wholly disagree with) doesn't really help. You are still invoking magic.

So your and her position is that SNPs barely matter at all?

Some do nothing at all (probably most), a few seem to have very significant effects (usually because they completely disable a critical enzyme) and some have a small effect.

This latter group includes most of the SNPs that get discussed over and over again on PR. The internet discussion of SNPs has completely distorted the significance of these small effects and convinced people that they have serious mutations that directly cause their health problems. There have been many scientific studies of many SNPs and they simply don't support this idea.

Well done association studies (not the early ones with small sample groups and inadequate statistics) do show a degree of association of some SNP combinations with various disease states, but the genetic contribution is small.

This doesn't mean I think SNPs are irrelevant. If I did I wouldn't have bothered to do a 23andme test nor spent considerable amounts of time understanding at least some of my SNPs.

Fortunately I don't seem to have any of the really serious SNPs but do have a mixture of ones known to have a small effect.

I see knowledge of these as something of an insurance policy - ie it is knowledge of potential weak points.

In healthy people who are eating well, they probably don't matter much. But we are not healthy and many of us are forced into very restricted diets because of food intolerances. Both of these circumstances (and especially the widespread metabolic derangements which seem to be associated with this disease) place our systems under strain and here weak points might manifest themselves. So if there is anything I can do to bolster the weak points I will do it.

This is not so very different from your idea that being sick has made a difference. Where I differ is that I don't attribute symptoms and sensitivities to particular SNPs, I don't single out some SNP as being the cause of some problem, particularly when there is no evidence for it and plenty of evidence to the contrary. I recognise that the endpoints that we perceive as symptoms have complex inputs, only one of which might be a small genetic contribution from various SNPs.

Where there is good reason to think that my combinations of SNPs might be contributing to slowing of an important metabolic pathway, and particularly when this is backed by functional data from an OAT, then I might decide to supplement cofactors for the affected enzymes and/or end products of the pathways, to help my struggling system.

I have COMT and MAO-A and definitely have problems with neurotransmitters

As already discussed, the MAO A variant makes a protein identical to the wildtype - ie the SNP has no effect. If you persist in ignoring things like this then you can't expect people to take you seriously.

Here is a post from Jack Kruse that might help explain it better

Jack Kruse is a neurosurgeon (? former) so I readily accept that he knows far more about the nervous system and related clinical matters than I do.

As for what he said in the quotes, this doesn't flow from that expertise so I don't just accept it. I want to know what it is based on. For example he makes claims for A1298C arising in equatorial regions, most particularly the East Africa rift zone or Mediterranean basin, in response to environmental conditions there. He goes on to say that we should look to the origins of our mitochondrial DNA to see if they accord with this.

I have this SNP and my heritage is almost exclusively from northern Europe (English and Irish). There is a tiny component from west-central Africa, presumably dating from more than 70,000 years ago before the African exodus.

So not especially convincing for me, though I could be persuaded to take him more seriously if he presented some genetic data about the incidence of this SNP, particularly among ancestral populations in East Africa.

So sorry, Jack Kruse doesn't help me much in accepting that COMT causes your methylfolate sensitivity.
 

sb4

Senior Member
Messages
1,654
Location
United Kingdom
No, not defensive in the slightest. I was simply astounded by what you seemed to be saying.

I am a tolerant and patient person and try to understand the point of view of others but your statements were just too much for me. I was expressing my astonishment.

Adding the qualification that a bad environment as well as degree of sickness might influence "expression of a SNP" (to use your terminology, but one I wholly disagree with) doesn't really help. You are still invoking magic.

I really don't see how I am invoking magic. I am simply saying enzymes might work better when they are created in healthy cells...

This is not so very different from your idea that being sick has made a difference. Where I differ is that I don't attribute symptoms and sensitivities to particular SNPs, I don't single out some SNP as being the cause of some problem, particularly when there is no evidence for it and plenty of evidence to the contrary. I recognise that the endpoints that we perceive as symptoms have complex inputs, only one of which might be a small genetic contribution from various SNPs.

So are you saying that, for example, COMT is in the correct position on the methylation diagrams but it effect is small, or that COMT SNP is just a random one that yasko has put there?

This is what I don't get, I'm agreeing with you on most points but I am saying maybe instead of some SNPs dont do much, I am saying they are only bad when other factors come into play. This would explain why these studies show that many people with for example COMT express no symptoms...


I have this SNP and my heritage is almost exclusively from northern Europe (English and Irish). There is a tiny component from west-central Africa, presumably dating from more than 70,000 years ago before the African exodus.

So not especially convincing for me, though I could be persuaded to take him more seriously if he presented some genetic data about the incidence of this SNP, particularly among ancestral populations in East Africa.

Same, I think he is saying that the SNP arose earlier on in our ancestory when it didn't matter, then we move out of the enviroment and then it starts to matter.

Anyway circadian rhythm, and UV + IR light have done a lot of good for me and I plus many others see them as being more important than SNPs. If you get those in check, the SNPs start to become less of a problem. I am simply saying if you are still struggling, maybe give it a try.
 

alicec

Senior Member
Messages
1,572
Location
Australia
am simply saying enzymes might work better when they are created in healthy cells...

Let's take COMT as the example. The V158M SNP results in a change from valine to methionine at position 158 in the COMT protein. These two amino acids have different properties and the change does affect the activity of the resultant enzyme.

The +/+ variant has about 1/3 less activity. From birth to death, THIS DOES NOT CHANGE. The SNP is ALWAYS expressed.

What might change is the cellular milieu in which the enzyme operates and this might make a difference to the impact of a sluggish enzyme.

So are you saying that, for example, COMT is in the correct position on the methylation diagrams but it effect is small, or that COMT SNP is just a random one that yasko has put there?

Why do you treat Yasko's diagrams as some sort of absolute reference point? She undoubtedly adapted them from someone else and made a hash of it.

The transsulfuration pathway is over-simplified and included a serious error which took years to correct, most of the folate cycle is missing and as for the egregious errors of the associated BH4, NOS and urea cycle pathways, don't get me started. These have never been corrected.

Let's look at what she says about COMT. She selects 3 SNPs as being of significance, V158M, H62H, P199P (I think these are her favourites, it's a long time since I looked at her stuff).

Well you should recognise by now that the last two have no effect. Why she decided they were important I have no idea but it makes me think she doesn't really understand how SNPs work. In a sense this is a random selection with no justification.

COMT is part of the degradation cycle for catecholamine neurotransmitters (and catechol estrogen and other substances but let's not complicate the issue).

It works by transferring a methyl group to a hydroxyl group on the catecholamine. SAMe donates the methyl group and magnesium is the co-factor.

If we travel to Yasko-land we are told that COMT +/+ (any of the SNPs whether they actually do anything or not) means that dopamine and noradrenaline are broken down slowly and SAMe is not used up, so all three accumulate. This leads to mood swings (from too many neurotransmitters) and sensitivity to methyl groups because of too much SAMe.

This is Yasko's version of reality, her idea of the consequences of COMT SNPs. It doesn't mean it actually happens.

She seems to have no concept of feedback inhibition and that it operates both within and between pathways. Levels of active substances like SAMe are monitored constantly and several mechanisms exist to control increase or decrease.

Neurotransmitters are even more tightly regulated at multiple levels (synthetic and degradative).

So the way she has written the actual steps of neurotransmitter degradation is in itself ok but her understanding of how this is linked to the methylation cycle is naïve if not downright ignorant.

As I said previously she demonstrates over and over again that she has a poor grasp of biochemistry.

There are plenty of good sources of information about COMT and other SNPs, I just don't understand why you let Yasko's mistaken notions form the benchmark for you thinking. I think you need to open your mind.

I also think this exchange has gone on for too long, so unless there is something absolutely pressing you need to say, let's just drop it.
 

sb4

Senior Member
Messages
1,654
Location
United Kingdom
Let's take COMT as the example. The V158M SNP results in a change from valine to methionine at position 158 in the COMT protein. These two amino acids have different properties and the change does affect the activity of the resultant enzyme.

The +/+ variant has about 1/3 less activity. From birth to death, THIS DOES NOT CHANGE. The SNP is ALWAYS expressed.

What might change is the cellular milieu in which the enzyme operates and this might make a difference to the impact of a sluggish enzyme.

Thanks, informative answer.

As I understand it enzymes work by proton tunneling, protons that come closer together tunnel better to improve functioning. Proton tunneling is improved by IR light (good mito), cold, and other things. Even with a faulty enzyme if you have say lots of IR building an exclusion zone of water condensing protons then tunneling will be improved to normal levels. If you got unhealthy the effects begin to show...
 

Jenny TipsforME

Senior Member
Messages
1,184
Location
Bristol
I've just been looking at https://codegen.eu/

It is free and the main advantage is it shows your risk compared to the rest of the population. This helps me to make sense of the often conflicting SNPs for the same condition. It also organises into categories like immune and aging. I suspect the wider categories are less useful as they must average out a lot of info.

What do you think of Codegen @Valentijn @alicec ?

Warning: you might be scared by your comparative risk! This is one of mine. There's hardly anyone who has a greater risk than me :eek::nervous:

zyera.jpg


I also have a few other leukaemia risks, though I wonder if these are SNPs which could be somehow associated with ME in a way we don't know yet?

Fortunately I bypassed my childhood leukaemia risks (and an unusual risk of reacting badly to childhood cancer drugs...). It may seem like we have bad health luck, but I suppose there are many times we're oblivious to the risks that pass us by.
 
Messages
15,786
It is free and the main advantage is it shows your risk compared to the rest of the population.
It might be useful - if the underlying data is reliable. Unfortunately SNP association studies suffer from a great deal of poor methodology. Hence I'm not going to believe that a SNP causes a tiny increase in some risk it until it's been replicated and/or subjected to appropriate statistical corrections.
 

ukxmrv

Senior Member
Messages
4,413
Location
London
Do other people mention this type of thing to your doctors?

I've not found a UK GP or NHS Consultant interested in these findings. Even when undergoing NHS testing for breast cancer risks the doctor was only interested in their tests and not potential things from other sources like 23andme
 

Jenny TipsforME

Senior Member
Messages
1,184
Location
Bristol
@ukxmrv I actually mentioned specific 23andme findings in an appointment with a neurologist this afternoon and it went down ok. But I think it will possibly lead to me having further NHS DNA testing.

This is actually entirely appropriate as the key causal SNPs are missing from the data :mad:, but I have quite a few of the associated SNPs. I'm getting referred onto a muscle specialist but the dr I saw today thought they might go straight to the DNA test rather than via a muscle biopsy, because of this insight. A DNA test would be much nicer for me!