GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby Hubbs » Tue Mar 08, 2016 1:00 am

@J11, thanks again for my much needed lucky break :D . Just before that I felt so defeated that I went on a dried pineapple feast. :oops:
E3/E4
MTHFR compound heterozygous (C677T and A1298C)
A1c5.7/LDL-P1602
All advices appreciated :)

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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby Silverlining » Tue Mar 08, 2016 2:36 am

J11, my father is doing very well. He's traveled the world in recent years including Africa, India, Fiji; just returned from Puerto Rico last month and heading out to Honduras next month. He flies frequently and also drives a behemoth RV cross country. Although he might not agree with this next statement; I felt like he was losing some focus during conversations a couple years back. But with his current regimen of low dose statin, metformin, video gaming, near daily exercise (racquetball, recumbent biking, treadmill walking) he's doing very well. He does have a chronic statin cough that bothers me much more than it bothers him :). Nothing much gets to him; he is blessed with a very laid back personality. He has two older sisters and one older brother; we do not know their apoe status. Two are doing well, one not so much. One of the sister's is showing MCI; I think she's 80. It's frustrating to me that we can't get to their genetics because I also believe more information is good! But they are completely uninterested, and of course I respect that opinion. I have a 92 yr old grandmother (maternal) with what I think you would term moderate dementia; she has no formal diagnosIs. I would love to have her genotyped as well....sigh.

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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby J11 » Tue Mar 08, 2016 6:37 am

Silverlining, thank you so much for posting this information!
This is currently perhaps the only partial indicator that the GG44 preventing dementia narrative might apply. n=1!
You might be able to use the fact that the whole world is waiting anxiously for an update on this as a bargaining
chip to encourage other family members to genechip. Typically people will not do such things as genechipping
that might be helpful for themselves, while they might for the sake of humanity.

If you look at Figure 2 from the below urls, you see that about 40% of 44s remain without cognitive impairment
over a ten year span from their mid 70s to mid 80s. The sample size used for the 44s is only 23, so there is quite a
bit of uncertainty what a larger sample would show. It would obviously be interesting to see how separating out the
GG44s might change the Figure. A cognitively intact 44 75 year old is not an entirely glaring outlier. Wonder what proportion
of those 40% are GG? Same question would apply to the cognitively intact 34s in their mid 80s, and the 33s in their 90s.

viewtopic.php?f=4&t=940&p=9729&hilit=TOMM40#p9729

For those not logged into the forum, here is the original url
http://www.alzheimersanddementia.com/ar ... 2470-4/pdf (page 3 of the pdf)

If anyone else could chime in with others with genotypes and phenotypes, then perhaps we could add some clarity to this question.

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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby LG1 » Tue Mar 08, 2016 7:05 am

J11:

My daughter and I have one of the newer versions of 23andme so it did not list results of rs9472817.

I am a 4/4 with all heterozygous for these three:

rs9381468 AG
rs9296504 CT
rs9381469 AG

My daughter is a 3/4 with all homozygous but if I am reading this thread correctly her results are not what we are looking for to possibly 'counter' the epsilon 4?

rs9381468 AA
rs9296504 TT
rs9381469 GG

I haven't properly reviewed the information in this thread so all I know at this point is there is some indication a person with the proper 'good' markers may have a chance to negate the epsilon 4 gene.

If there is a nutshell explanation that would be awesome. I will otherwise get stared on my research.

Thanks!
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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby J11 » Tue Mar 08, 2016 9:03 am

Lg1, yes you are quite right a clear summary of the facts as they are now known would be helpful.

The study found that the minor allele (that is, G) of rs9472817 in the SLC25A27 gene appeared to reduce AD risk in epsilon 4 carriers.
This study likely had few if any epsilon 44s, so it is very unclear whether the result applies to them.

For those without this SNP on their genechip, the workaround is the SNP rs9381468.
The minor allele (that is, G) of rs9381468 should equate to the G allele of rs9472817.
This should give good, though not perfect predictive power.
The minor alleles of rs9296504 (that is, C) and rs9381469 (that is, A) might help to improve the prediction.

We could go to OpenSNP or 1000 genomes to confirm that the accuracy of this approach.

At this point the result needs to be treated as highly speculative, there have been thousands of previous such claims that have
nearly without exception been subsequently proven to be completely wrong. Even if the thin chance that this is actually true holds,
it would be expected that the true benefit would be much less than has been reported.

The 80% of people who have been made miserable by this news really should cheer up! :D
As I have mentioned, it probably isn't correct.

Also, my objective assessment is that a defect such as this seems fixable.
Many genetic variants (for example, epsilon 4) have been studied for decades and it is still not clear what the underlying biological
problem is. The biology of Uncoupling Proteins seems much simpler. These proteins uncouple the mitochondrial proton motive force: Simple!
(Anyone care to give a one sentence biological description of what APOE does?)

I see this more as a great learning moment.

First, we clearly need a freely accessible database of AD genotypes and phenotypes.
The researchers of the current study had to go on a hunch and gamble a fair chunk of change to try and prove their point.
This puts a substantial barrier to solving the genetics of Alzheimer's. Whoever authorized the spending must have realized that this
had lottery odds of paying off. If they could have run this first through a database, then they would have significant confidence that it would work out for them. It is quite surprising from a financial perspective that this is not done. It is taxpayer's money: our money.
Why isn't there an AD database? Don't the Alzheimer's patients who donated their DNA samples for this research at some level "own" their
DNA and the informational value that is locked up in restricted access computer servers? Should not their rights concerning possible disclosure of their data be respected. We would not have to go through this somewhat traumatic process of sorting through all these variants if we could now access such a database. The truth about the 817 SNP could be known immediately.

We need an open AD database.

Secondly, this also highlights for me the importance of people knowing their genetics. There are quite a few out there that must be hoping that they were GG. Once AD genetics has been definitively unraveled, there were quite likely be a variant ( rs9472817 or otherwise) in which people will wish that they had it. I know how tough it would be in this age of genetics knowledge to look at one's child and realize that by some unfortunate accident they got the wrong allele. If enough people were aware of being in this circumstance (by being genotyped), then we really could take the future into our own hands.

The answer is of course obvious.
Why not just change the genetic mistake?
Why not CRISPR?

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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby LG1 » Tue Mar 08, 2016 9:36 am

J11 said...
The 80% of people who have been made miserable by this news really should cheer up! :D
As I have mentioned, it probably isn't correct.


No worries here. I'm not one to wring my hands at every bit of potential bad news.

It's a pleasure to have you do all the hard work though!

Knowledge is Power!
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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby J11 » Tue Mar 08, 2016 10:38 am

LG1, that feels great!
In an instance like this, one worries whether the messenger could outrun all the angry townspeople.

Those on the forum have chosen to bite the apple.
There are no returns for apples with bites in them!

I surely agree with the Knowledge is Power idea.
Someone will have this power, why not the people?
It appears that there is now a completely futile attempt by the elite to usurp this power for themselves.

It is very difficult to imagine that a rational person would prefer to first learn of their dementia status
when they had already slipped into a clinical diagnosis.

By knowing beforehand, one could make an informed choice under Right to Try legislation on how best to proceed.
CRISPR has already been perfected, so it should not be a large mystery how this could be corrected.

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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby LG1 » Tue Mar 08, 2016 12:30 pm

J11:
I surely agree with the Knowledge is Power idea.
Someone will have this power, why not the people?
It appears that there is now a completely futile attempt by the elite to usurp this power for themselves.


HA! Brings to mind some previous posts on a thread discussing that ridiculous Harvard study claiming there should be no testing. I had to put it out of my mind because it had me seething (which is bad for us).
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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby J11 » Tue Mar 08, 2016 3:20 pm

Well, this probably should be news to no one on the forum, though sometimes it is important to expliciticate (is that a word? Is now.)
the implicit. The epsilon 4 community possesses the demographic and sociopolitical strength that no other interest group can match.
The best strategic choice for other disease communities would be jump on the epsilon 4 bandwagon. For some reason epsilon 4 was the ancestral genotype and still occurs with considerable frequency. It would be difficult to imagine for example, a cancer variant as being ancestral. There might be some counterintuitive reason why epsilon 4 had been selected in our primate ancestors, though it is difficult to imagine many other illnesses being likewise selected.

Those who want epsilon 4 genotypes to remain obscure to the carriers perhaps can clearly see and want to avoid the approaching epsilon 4 political dominance. People with firmly entrenched goals are typically undefeatable.

I have been reading up on NUMTs. What you may ask is a NUMT? "(Nuclear MiTochondrial Sequences) are mitochondrial DNA sequences that, after stress events involving the mitochondrion, colonized the nuclear genome."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314570/

This is of interest because mitochondria have considerable relevance in dementia pathology.
I had been somewhat confused before, when looking through our loved one's exome file.
The mitochondrial sequence was almost completely clear of variants. This did not make sense to me.
However, my recent uncovering of NUMTs could be the missing link.
NUMTs are mitochondrial genes that have migrated to the nucleus.
Humans have hundreds of them.

The second to last track near the bottom on the below url is labeled Human NUMTs.
What I find odd is that as can be seen on the tracks toward the top, the genome browser is lined up around 46.7 MG on chr. 6 and is showing the SLC25A27 gene. Why isn't SLS25A27 being noted on the Human NUMTs track as a NUMT? The function of the SLC25A27
is as an uncoupling protein on the mitochondrial electron transport chain. How much more mitochondrial can it get than that?

https://genome.ucsc.edu/cgi-bin/hgTrack ... 5AXKGyo1Nf

It will be great if we can find a current url that has organized all of these NUMTs into a neat database.
Such nuclear control sequences of the mitochondria could be substantially important in AD.
Perhaps such a database might include putative NUMTs as UCP-2,3,4,5?

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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby J11 » Tue Mar 08, 2016 7:24 pm

"In the cells of extant organisms, the vast majority of the proteins present in the mitochondria (numbering approximately 1500 different types in mammals) are coded for by nuclear DNA," Now that is very interesting. Human nuclear DNA is almost 10% mitochondrial transfers?

https://en.wikipedia.org/wiki/Mitochondrial_DNA

Sure would be great if there were a list somewhere for all these genes.

Now, for some background on the uncoupling proteins.
The uncoupling proteins create a leak in the mitochondrial membrane.
The G variant 817 is increasing this gene expression.
What seems to be happening is similar to opening a window on a cold winter day.
The furnace is going to get a good workout.

For a strange counter-intuitive reason having a broken uncoupling protein might help prevent dementia.
However, as some of the research points out this would not always be helpful.
If other uncoupling proteins were to be broken you could wind up with futile thermal generation and this might
lead to the serious problem in cancer patients of cachexia.


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