Genetic association study in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) identifies several potential risk loci, 2022,Hajdarevic et al

Interesting - I wonder if the research into Alzheimer's may help - understanding how to investigate abnormalities in brain cells - potential ways to treat. Sounds optimistic - understatement, but they may have come up with techniques/technologies which could help to understand e.g. TPPP1 functioning.
 
Peter Trewhitt said:
Sometimes I find delayed PEM, even with rest, can paradoxically get worse over several days following its onset. Often when this happens it is when PEM feels most like a virus or a hangover. It can have a sense that my body thinks there is something it needs to get rid of, rather than a lack of something. Then it may build up to a severe migraine like headache which worsens till I vomit and/or have explosive IBS, when sleep becomes possible and then with rest my PEM begins to subside.

Sometimes PEM feels like a lack of something but other times it feels like a build up of something that should not be there. Could problems relating to a specific protein metabolism result in a shortage of something or an excess or unwanted presence of something or a combination of both?
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I find it very hard to describe this, even when it is happening I have tried to find words but to no avail. When I am particularly exhausted, usually because of lots of sensory input such as my grandchildren moving, shouting, playing arguing, tv on, all talking to me at once - you get the picture - I lie on the bed hardly able to think then something comes over me like a glass filling up, fizzing, building and building till it breaks the way a fever breaks and I start to feel better.

In the days when I was moderately ill but had young children so the PEM was often worse, I would find tears running down my face which I assumed was my body desperately trying to get rid of toxins.

In those days I also experienced a strange thing when I was exhausted. A black depression would creep over me in the course of a few hours but if I slept, even for just a few minutes, I would waken up with it gone.

ME is much more complex than "fatigue"
 
Mithriel said:
I find it very hard to describe this, even when it is happening I have tried to find words but to no avail. When I am particularly exhausted, usually because of lots of sensory input such as my grandchildren moving, shouting, playing arguing, tv on, all talking to me at once - you get the picture - I lie on the bed hardly able to think then something comes over me like a glass filling up, fizzing, building and building till it breaks the way a fever breaks and I start to feel better.

In the days when I was moderately ill but had young children so the PEM was often worse, I would find tears running down my face which I assumed was my body desperately trying to get rid of toxins.

In those days I also experienced a strange thing when I was exhausted. A black depression would creep over me in the course of a few hours but if I slept, even for just a few minutes, I would waken up with it gone.

ME is much more complex than "fatigue"
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I can relate to all you say Mithriel, that is a good description.

Thats again why i hate the 'fatigue' word. But i dont want to get my on my soap box about that haha!
 
Mithriel said:
I find it very hard to describe this, even when it is happening I have tried to find words but to no avail. When I am particularly exhausted, usually because of lots of sensory input such as my grandchildren moving, shouting, playing arguing, tv on, all talking to me at once - you get the picture - I lie on the bed hardly able to think then something comes over me like a glass filling up, fizzing, building and building till it breaks the way a fever breaks and I start to feel better.

In the days when I was moderately ill but had young children so the PEM was often worse, I would find tears running down my face which I assumed was my body desperately trying to get rid of toxins.

In those days I also experienced a strange thing when I was exhausted. A black depression would creep over me in the course of a few hours but if I slept, even for just a few minutes, I would waken up with it gone.

ME is much more complex than "fatigue"
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I often have the same feeling, which I describe as despair. It can be over something as small as dropping a pencil on the floor. That is my signal to go have a nap. In the same way, even a short nap makes the feeling go away. The precursor seems to be an irritability about everything. Now my partner even suggests it when I get chippy.

The first time I took Lyrica I woke up the next morning feeling like a miracle had happened. I assume it was the first decent sleep I'd had in a long time. The Lyrica gave me about two years, with gradually increasing doses. Eventually I just got a lot worse. Now I recognize a doubling of dosage as a sign that I've probably encountered a stimulant which is going to wear me down.

I started using THC drops at night (I'm from Canada). The first few times I used it I would wake up eight hours later, long after the effects should have worn off, and wonder if I was somehow still high. Eventually I just realized that's how people feel after a good sleep.

People also forget that stimulation is also a problem, no just physical exercise. The brain uses a lot of energy. I spend a great deal of my day lying down in a quiet room. No television. No radio. No reading. It is really boring but it allows me to have a few hours of family time in the evening.
 
THC 32mg/g CBD 0.0
The 30ml bottles come with a syringe that stops a standard dose at .3ml, which is about 3 drops. I've never used more than one standard dose.

The CBD bottles are
CBD 100mg/g
THC < 3mg/g

I also use the CBD occasionally on days where I might have to drive. I find even with a dosage of 3 or 4 times as much I don't get the same effect.
 
Reading up on the things microtubules / tubulin is involved in, is interesting. It's involved in the regulation of cellular energy metabolism and mast cell degranulation and probably many other functions.

The link to energy metabolism is the role it plays in the cytoskeleton. It appears that the specific organization of the cytoskeleton, shape of the cell and these kinds of things influence energy metabolism of the cell.

I'm guessing that red blood cell deformability also has something to do with these kinds of structural proteins.
 
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Lupus analogy is helpful in understanding the value SNP findings in GWAS

This analogy from Jonathan Edwards, about how a deficiency of one protein in the complement system revealed the importance of the complement system as a whole in causing Lupus, is very helpful in understanding how GWAS work.

Jonathan Edwards said:
I don't think anyone was saying that this SNP would account for most ME.
I see it as a bit like C1q deficiency, which accounts for a tiny proportion of cases of lupus but provides a hugely powerful piece of evidence for the importance of complement in the genesis of lupus.

It turns out that there are a number of other ways to get C1q to malfunction in lupus, probably mostly not genetic. There might be lots of other ways to get tubulin assemblage to malfunction - which again may not be genetic. But if thee is a genetic weighting to a variant in TPPP that ought to be telling us something very important.
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Each SNP that is significant may play only a trivial role: it's more like a flag pointing out a gene that might play an important role. Usually, scientists would want to see several SNPs point to the same gene (or the same pathway) before they get excited.

Usually, SNPs only affect the amount of gene expressed: the protein is completely normal, and the biological effect is subtle. Compare this with a genetic disease, say sickle cell disease, where the haemoglobin gene defect affects the nature of the protein that is made (so that it binds oxygen less well). Such changes to the protein can have a much bigger effect.

Jonathan Edwards said:
But if DecodeME pulls out the same site it would be something major - even if the DecodeME statistical analysis in isolation is also inconclusive.
If it is spurious DecodeME should draw a complete blank - that is not guaranteed but it is pretty robust, as long as you take into account the number of test points linked to the site of interest. The problem of multiple analyses remains a factor.
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That's why using p< 5 x 10^-8 as the statistical threshold is so important as it corrects for the many comparisons. This study finding falls an order of magnitude short of that threshold.
 
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Thank you for the explanations! Do you (Simon, Chris or anyone) know if they reported on rs7337312 ( SLC25A15 ) which looked somewhat promising from a previous UK biobank analysis? I couldn't see anything from a cursory look at their supplementary data
 
Forbin said:
A question I’ve never really thought of before is… if you get delayed PEM (next day PEM) does it gradually begin to improve on that day, or does it only begin to improve after another sleep cycle?

I would say the latter.

[I’m not saying it will fully resolve after another period of sleep, just wondering if it won’t start to get better before another period of sleep.]
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ime this is key. i have a more nuanced and detailed response someplace but don't have it in me to search for it atm. sleep, including but not limited to circadian stuff, mediates pem. and pem can make sleep worse.
 
Samuel said:
ime this is key. i have a more nuanced and detailed response someplace but don't have it in me to search for it atm. sleep, including but not limited to circadian stuff, mediates pem. and pem can make sleep worse.
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It's difficult to exclude correlation. If PEM is mediated by an elapse of time - it is classically described as occurring many hours after an assumed precipitating activity/event - then in any individual where onset of PEM is perceptible after an elapse of time which includes the usual sleep pattern, onset of PEM will appear correlated with sleeping.

That isn't to say there is no interaction between the process of sleep and the process of PEM but it seems difficult to easily separate those interactions. A further confounder might be the restart problem where in ME/CFS moving from a lower activity state to a higher activity state is notably difficult. If PEM is a cumulative response, that is it is a process that builds over a period of time, restarting - in this case waking/getting up in the PEM state, will be notably more difficult than waking/getting up in the non PEM state, providing a 'day after' effect.

I'm a 48 hour PEMer - so typically I will have two night time sleeps (no day time ones) before PEM becomes a notable feature.
 
JemPD said:
I've shared elsewhere on the forum how anxiety/anger and the resultant significant improvement in all symptoms (assumed to be from adrenaline release) can fool me into thinking i better than i am - and therefore sometimes wrongly believe that the bout of PEM is over leading to further activity instead of rest, leading to worse PEM later.

Just wondering how adrenaline (or some other process/signalling triggered by the sympathetic nervous system response) might affect the tubulin processes.

@Jonathan Edwards is there a way for that to fit in, or to be explained within the tubulin/ TPPP issue we're discussing here (lol sorry dont know what to call it, the details of all this are a bit beyond me!)
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I've recently been thinking a bit about how adrenalin seems to improve function/reduce PEM for me, and also about myelin integrity, so your question is interesting.

There's this recent paper:
Microtubule and Adrenaline Interaction: A Key Source to Understand Conscious Balance in a Human Body, 2024
They seem to have done spatial computer modelling of molecules.
Adrenaline docked successfully into Microtubule Associated Proteins (MAPs), alpha and beta tubulin and microtubules. The present study also led to an interesting observation that Microtubules stability increased when Adrenaline docked into Microtubules. From the present docking study it is hypothesized that Microtubules and Adrenaline together control brain activity and help to maintain the conscious state of the being at physical level.
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So, adrenalin may make microtubules more stable.
 
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Low SNP frequencies surprised my non-scientist eyes; for example, directly genotyped tagSNP rs115523291 had:
a) Norwegian allele frequencies of 2.5% and 0.4% for MECFS/normal, P=8.5X10-07
b) UK 1.0% and 0.9% P=0.03

I take it those sorts of frequencies are nevertheless potentially significant, in light of Jonathan Edwards' comments:
Jonathan Edwards said:
I don't think anyone was saying that this SNP would account for most ME.
I see it as a bit like C1q deficiency, which accounts for a tiny proportion of cases of lupus but provides a hugely powerful piece of evidence for the importance of complement in the genesis of lupus.

It turns out that there are a number of other ways to get C1q to malfunction in lupus, probably mostly not genetic. There might be lots of other ways to get tubulin assemblage to malfunction - which again may not be genetic. But if thee is a genetic weighting to a variant in TPPP that ought to be telling us something very important.
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Should the "typical" genome-wide significance (P < 5×10−8) be even smaller for the p-values for the imputed SNP genotypes in the association analyses?
 
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