New study finds vast majority of diseases have only a very small genetic contribution of 5% to 10% at most (so much for 23andme testing)

[Hip]

By the way, I think the poliovirus vaccine explanation for the the large increase in ME/CFS in the 1980s is a viable explanation. It's not that the poliovirus vaccine itself is dangerous; it's not. But the theory is that when the poliovirus vaccination program was introduced, it prevented children from being naturally exposed to wild poliovirus.

Wild poliovirus exposure is thought to train the immune system to better deal with any subsequent enterovirus infections. So if you are naturally exposed to poliovirus (which is an enterovirus), as most children used to be before the vaccination program, then when you catch an ME/CFS-associated enterovirus later in life, your immune system more efficiently handles it. But without this natural exposure to poliovirus, the immune system has not yet learnt to deal with enterovirus infections, so it struggles harder to control the virus.

If the immune system is struggling to control an enterovirus infection, that may give the infection more opportunity to infect critical organs such as the brain, and thereby cause ME/CFS.

Corroborating evidence for this idea that prior natural poliovirus exposure helps fight any subsequent enterovirus infections comes from type 1 diabetes (T1D) prevalence data. T1D of course is linked to enterovirus infection of the insulin producing cells of the pancreas.

In Estonia, rates of T1D are 3 times lower than in its neighbor Finland (ref: here). Why? Well, Estonia uses a live poliovirus vaccine, which is closer to natural wild poliovirus infection, and so vaccination confers some future protection from enterovirus. But Finland uses the killed poliovirus vaccine, which does not simulate a natural infection. Thus Finnish childrens' immune systems do not get trained to deal with enterovirus, and so they have less protection against getting diabetes.

 

[Rufous McKinney]

that is if you are getting ME/CFS after reproductive age, then evolution pretty much doesn't care what happens,

There were potentially adaptive benefits through natural selection for traits such as living beyond one's reproductive years (in females, menopause), having older members with in your group (wisdom, experiences which increase survival), selection for being more sensitive (about 18%).

Maybe folks with less energy and vigor- were better at watching toddlers. Or making implements and fish hooks.

But I do think much of our ME problem stems mostly from the second whammy of Environmental Toxin exposure, which can include the antibiotic disruption of the developing gut, and all the other exposures.

And that also betters explains why it was so very important to not recognize ME as a disease. Humans can take a place like Lake Tahoe- a stunning crystal lake of once pristine beauty- and turn it into Pea Soup. (thats what we call a lake turned green and full of cyanobacteria).

 

[hopeforaday22]

Very interesting...

But I remember a study from about a year ago, which mentioned that many had mutations in genes which causes glycogen storage disease, or variants that cause problems with making normal energy...

Oh, I found it:

https://www.healthrising.org/blog/2...s-energy-production-chronic-fatigue-syndrome/

 

[wigglethemouse]

Very interesting...

But I remember a study from about a year ago, which mentioned that many had mutations in genes which causes glycogen storage disease, or variants that cause problems with making normal energy...

Oh, I found it:

https://www.healthrising.org/blog/2...s-energy-production-chronic-fatigue-syndrome/

The study at the time was preliminary and only a handful of patients. Glycogen storage disease normally requires damaging variants of both copies of the gene. If I remember right the participant only had one copy with a variant. With two damaging copies that would point to a clue for a doctor to test specific clinical tests for that type of glycogen storage disease to see if in fact that gene is a cause or enabler of the disease.

As the article in the original post of this thread suggests we really need detailed metabolomics and proteomics to tie in with genetic variants to give us a better picture. Those tests with enough specifics are not available outside of a research environment.

ETA: It was 2 out of 10 patients that had a glycogen storage associated variant. One variant had no gene data associated with disease, the other was on gene ENO3 gene associated with mild disease. See slide at 40mins and intolerance to exercise.

 

[ebethc]

@Hip

So much for 23andme? I beg to differ... I have:

• hemochromatosis caused by HFE genes
• Factor 2, caused by F2 genes
• KIT genes predisposing me to MCAS
• 14 thyroid genes with about 200 mutations and I have thyroid issues
• Genes that lead to low folate, low B12, low tetrahydrobiopterin, low MnSOD, and low vitamin D

What are the rs #s for the KIT genes?

 

[wigglethemouse]

What are the rs #s for the KIT genes?

The clinical variant test is for KIT D816V rs121913507. Some papers discuss other KIT variants could have an effect too.......

Here is ClinVar for this variant
https://www.ncbi.nlm.nih.gov/clinvar/variation/13852/

And ARUP clinical test
https://ltd.aruplab.com/Tests/Pub/3000440

 

[ebethc]

The clinical variant test is for KIT D816V rs121913507. Some papers discuss other KIT variants could have an effect too.......

Here is ClinVar for this variant
https://www.ncbi.nlm.nih.gov/clinvar/variation/13852/

And ARUP clinical test
https://ltd.aruplab.com/Tests/Pub/3000440

bummer... not in 23andme... thanks for the info, though

 

[ebethc]

I think the reliability of that figure is poor, since we didn't have any way to properly diagnose ME then, and still don't. Many reported cases might not be ME, and there's no real way to know how many unreported cases there are.

I wonder if there are any medical historians who can find out whether there were cases (or epidemics) of ME at different times in the past. It would be really interesting if there was nothing clearly matching ME until something like DDT was in widespread use.

exactly... and it's had other names over the decades/centuries ("neurasthenia"). 2nd, it's more than 1 illness IMO, so as ppl become diagnosed w something else, they are removed from CFS designation...

 

[pattismith]

According to Ewald, the genes that cause these genetic diseases will have only propagated down the generations because they provided some compensating evolutionary survival advantage.

For example, this paper posits that the hemochromatosis genes which cause excess iron retention may have appeared when European Neolithic humans migrated northwards into colder climates, because these genes allowed for better thermoregulation in the cold.

We still pay our neolithic revolution and the associated diet change (heme iron deficient diet). It's not only the climate change. Iron from vegetable sources is poorly absorbed.

Porotic Hyperostosis in Neolithic Greece: New Evidence and Further Implications on JSTOR

About HFE gene and it's adaptative effect to increase iron absorption, there is a very interesting 2020 study in US/Canada.
I suspect red meat consumption to be the main factor negatively associated to iron deficiency...

Abstract
Background
Few cross-sectional studies report iron deficiency (ID) prevalence in women of different race/ethnicity and ages in US or Canada.

Materials and methods
We evaluated screening observations on women who participated between 2001–2003 in a cross-sectional, primary care-based sample of adults ages ≥25 y whose observations were complete: race/ethnicity; age; transferrin saturation; serum ferritin; and HFE p.C282Y and p.H63D alleles.

We defined ID using a stringent criterion: combined transferrin saturation <10% and serum ferritin <33.7 pmol/L (<15 μg/L).

We compared ID prevalence in women of different race/ethnicity subgrouped by age and determined associations of p.C282Y and p.H63D to ID overall, and to ID in women ages 25–44 y with or without self-reported pregnancy.

Results
These 62,685 women included 27,079 whites, 17,272 blacks, 8,566 Hispanics, 7,615 Asians, 449 Pacific Islanders, 441 Native Americans, and 1,263 participants of other race/ethnicity.

Proportions of women with ID were higher in Hispanics and blacks than whites and Asians.
Prevalence of ID was significantly greater in women ages 25–54 y of all race/ethnicity groups than women ages ≥55 y of corresponding race/ethnicity.
In women ages ≥55 y, ID prevalence did not differ significantly across race/ethnicity.

p.C282Y and p.H63D prevalence did not differ significantly in women with or without ID, regardless of race/ethnicity, age subgroup, or pregnancy.

Conclusions
ID prevalence was greater in Hispanic and black than white and Asian women ages 25–54 y. p.C282Y and p.H63D prevalence did not differ significantly in women with or without ID, regardless of race/ethnicity, age subgroup, or pregnancy.

Prevalence of iron deficiency in 62,685 women of seven race/ethnicity groups: The HEIRS Study (plos.org)

 

[Learner1]

We still pay our neolithic revolution and the associated diet change (heme iron deficient diet). It's not only the climate change. Iron from vegetable sources is poorly absorbed.

View attachment 45558

Porotic Hyperostosis in Neolithic Greece: New Evidence and Further Implications on JSTOR

About HFE gene and it's adaptative effect to increase iron absorption, there is a very interesting 2020 study in US/Canada.
I suspect red meat consumption to be the main factor negatively associated to iron deficiency...


Prevalence of iron deficiency in 62,685 women of seven race/ethnicity groups: The HEIRS Study (plos.org)

Hemochromatosis can get triggered later in life, particularly with menopause, which is not common in women age 25-54. The oldest part of that bracket, yes, but not the younger women.

 

[pattismith]

Hemochromatosis can get triggered later in life, particularly with menopause, which is not common in women age 25-54. The oldest part of that bracket, yes, but not the younger women.

Yes, it's well known that iron deficiency in women is less prevalent after menopause, because of cessation of menstrations:

.

Prevalence of ID was significantly greater in women ages 25–54 y of all race/ethnicity groups than women ages ≥55 y of corresponding race/ethnicity

However, in some women iron deficiency remains a problem after menopause. I am 2 years post menopause, and my ferritine is still low

 

[Learner1]

Yes, it's well known that iron deficiency in women is less prevalent after menopause, because of cessation of menstrations:

.

However, in some women iron deficiency remains a problem after menopause. I am 2 years post menopause, and my ferritine is still low

I was responding to the idea that women with the main HFE hemochromatosis genes are iron deficient, and not having the expected iron overload. I suspect that menstruation was likely contributing to the iron deficiency in the study you shared.

In my case, even though I have those HFE mutations, my ferritin was always normal until my hysterectomy stopped a monthly loss of blood, and within 18 months, my ferritin was above 600, when 60-100 is normal. Iron overload can damage organs and lead to death, so well worth monitoring.

Many women are anemic. This can be due to gut malabsorption or excess blood loss.

 

[2manyhobbies]

tl;dr ... averages suck b/c they're not that meaningful or actionable
-
Re CFS: whatever is wrong w my health is definitely genetic....
I'm adopted and was raised by parents who were extremely health conscious... My adoptive mother and her family are VERY intense exercisers (marathoners, etc) and diet means "calories in vs calories out" w plenty of veggies, and what most americans would consider a "sensible diet"... She's 5'5" 100 lbs and has never counted a carb in her life or bought organic anything... She has a lot of health problems in her family that I don't have, and eating low calorie diet w a ton of cardio exercise keeps her healthy...eg She's avoided the cancer that 3 of her siblings have had... (2 recovered, 1 didn't. 1 of the siblings who recovered is a health nut, too, but the other one only plays golf for "exercise"..The one who died was the only sibling in the family who eats bad and doesn't exercise..).. She def raised us to get nutrients from food vs pills/supplements. She believes that good health is discipline and sensible choices (yes, but sometimes NOT).

I met my biological mother in college, and she + her oldest daughter have a symptom overlap w me of ~90%. they live in a different part of the country than me, and she raised her family all over the world due to her husband's profession (ie, how much is really environmental??). She seems health conscious, but I didn't grow up w her so I can't say to what degree (ie, my adoptive mother is OBSESSED w health)... So, lifestyle and choices can't be blamed for everything.

With that said, I could be doing something "wrong" every day because I don't understand what the problem is.. I wouldn't be on this board if I didn't think there's something to understand and change. Taking care of yourself is extremely important, but what does "taking care of yourself" even mean if you're the canary in the coal mine? We're all on PR to share our n=1 experiments, trying to find out.

Re Huntington's Disease (as an alternative example):
I have a friend whose wife has Huntington's disease, which is VERY much a genetic disease... He has two kids and is worried sick they have the gene... He hasn't had them tested b/c it's their choice when they're old enough to decide. He works tirelessly on fundraising to find a genetic-level cure..
https://www.hda.org.uk/huntingtons-disease/what-is-huntingtons-disease/genetics-of-huntingtons-disease#:~:text=One of your parents is,75 % chance of inheriting it.

Re Genetics, 23andme, etc.: I think it's the COMBO of genes that screws you over....
I'm surprised ppl don't acknowledge this or see it more... and I wonder if AI will help us understand this better.. e.g., ppl look up one gene in 23andme and don't necessarily understand the whole pathway... I think our bodies are incredibly adaptable and if something's broken along some pathway, we can adapt to accommodate the problem, BUT, if you have the wrong COMBO of bad genes, your body can't overcome being repeatedly thwarted and breaks down .. so looking at a discrete gene can really send you down a rabbit hole...

Exactly, I think the medical community is always- repeat always- trying to tell us it would not matter it was just in the cards for us. I do strongly believe Snps have a strong influence on our overall health They are an important part in which foods we choose, which exercise is best for us.

23 and Me is chuck full of raw data that needs to be unraveled to be of use. In my own case I have a strong family history of heart disease and wanted some answers, especially after a second cabg. I did 23 and Me then sent the results to A.J. Consulting for a breakdown.

Seems I have a couple Snps that magnify my chances of heart disease 10X--if my heavy metals are high. I have a concurrent CBS Snp that slows down glutathione production and slows expulsion of metals--BINGO' The SOD2 gene isn't serious if heavy metals are kept in check. The report and phone consultation revealed several other important pieces of information but this was MY kryptonite.

 

[2manyhobbies]

Yes, it's well known that iron deficiency in women is less prevalent after menopause, because of cessation of menstrations:

.

However, in some women iron deficiency remains a problem after menopause. I am 2 years post menopause, and my ferritine is still low

But what is low? If you have enough ferritin to keep hemaglobin in the average normal range- say 14-16, I wouldn't be too in too big of hurry to increase ferritin. Part of the reason women are protected from heart disease and cancer( to an extent) premenopausal is that their ferritin levels are kept below 100 ng/ml from monthly periods. Ideally ferritin levels of 60-80 are most protective and all that is needed for rbc formation.

 

[pattismith]

But what is low? If you have enough ferritin to keep hemaglobin in the average normal range- say 14-16, I wouldn't be too in too big of hurry to increase ferritin. Part of the reason women are protected from heart disease and cancer( to an extent) premenopausal is that their ferritin levels are kept below 100 ng/ml from monthly periods. Ideally ferritin levels of 60-80 are most protective and all that is needed for rbc formation.

my ferritin was still at 20 ng/ml .
I have Restless legs, and low iron is a well known risk factor.
For restless legs people ferritin should be raised to 75 and more.
For cardiac deficiency people ferritin should be raised to 100 and more;
These are the official medical recommandations.

 

[SWAlexander]

if you have the wrong COMBO of bad genes, your body can't overcome being repeatedly thwarted and breaks down .. so looking at a discrete gene can really send you down a rabbit hole...

Exactly. It takes quite some time and study to understand how to read 23andme. A Promethease report can be a big help. On top, there is the possibility of epigenetics.

 

[2manyhobbies]

my ferritin was still at 20 ng/ml .
I have Restless legs, and low iron is a well known risk factor.
For restless legs people ferritin should be raised to 75 and more.
For cardiac deficiency people ferritin should be raised to 100 and more;
These are the official medical recommandations.

Respectfully Patti: Where did you find the reccommendations cited for cardiac deficiency and restless legs?

 

[pattismith]

Respectfully Patti: Where did you find the reccommendations cited for cardiac deficiency and restless legs?

Criteria for Iron Deficiency in Patients With Heart Failure | Journal of the American College of Cardiology (jacc.org)

Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force report - ScienceDirect

 

[datadragon]

We have now learnt that faulty genes rarely cause disease; at best faulty genes might mildly predispose us to a disease. But they certainly are not a viable explanation for why common diseases arise.

Genetics can cause disease in certain cases, but for most people I agree that they mainly can predispose you. As an example I will use a little known obscure condition called Autism. Many genetic variants have been linked to autism, but only a handful are potent enough to induce the disorder on their own. Among these variants, mutations in a gene called Shank3 are among the most common which accounts for around 2% of all ASD cases. Shank3 knockout mice show the triad of core ASD symptoms. However what I found was that the main underlying cause for the rise in autism cases is that both inflammation and zinc deficiency happen to converge to also lower shank3 levels, explaining why there is such a wide variety of contributors to autism development since there are so many factors that can induce inflammation (NLRP3 activation) or zinc deficiency. Further, the shank3 gene itself regulates intestinal barrier function, and also zinc uptake in the gut. The protein encoded by the SHANK3 gene, a gene that is known to cause autism by itself, also turns out is regulated by zinc.

 

[datadragon]

ppl look up one gene in 23andme and don't necessarily understand the whole pathway...
Seems I have a couple Snps that magnify my chances of...

Yes the first sentence is good. A main important thing to note is not to necessarily focus on "I have a mutation therefore its bad and I need to fix it". Many genetic mutations seem to normally be there for a reason. Many genes I found are part of the larger picture in how the body may compensate for something else going on in other linked pathways. First note how many of the total snps for a gene are even mutated, some people find just a few out of say 50 may not necessarily even have any impact, when if 2 out of 4 are mutated that may have more impact. Sometimes however there will be research that points to specific effects of having mutations in a specific snp of a gene and that can be taken into consideration. However you would have to look again at all the other linked pathways to see what may be changed also to compensate for that effect. Also the gene effects may have been looked at in isolation, same problem when they look at one component of a food or oil to study its effects by itself when its not alone.
That is why bypassing mutations such as by taking active forms of vitamins without understanding that may work against you in some cases as the mutations may be present for a good reason, something that it took several years of research for me to finally figure out.