Unfolded Protein Response and A Possible Treatment for CFS

[Gondwanaland]

Rooibos tea increases T 43%.

I thought they gave it to restless babies in South Africa

Edit -- http://examine.com/supplements/rooibos/

 

[Tunguska]

I haven't tried it, i only quitted Choline two days ago.

I would simply take choline forever. From food or supplements, at least 500mg a day, just varying the form. Read enough sources that say the general population doesn't get enough, and the "adequate intake is 550 mg/day for men". Somewhere between 400-1000mg is normal. 500mg taurine perpetually or a bit less is likely good prevention too.

Inositol is not worth it when you look at the food sources.

 

[mariovitali]

I am currently looking at programming with an R Code that we can all use. I will post more soon.

@Valentijn

The Code uses the Bioconductor R Package. Since i want to test the validity of the output :


Could you tell me -based on your knowledge- whether we can conclude that a CEU individual having (G;G) for rs10067427 has risk to develop NAFLD?

See here : http://www.snpedia.com/index.php/Rs10067427


Thanks in advance

 

[Valentijn]

Could you tell me -based on your knowledge- whether we can conclude that a CEU individual having (G;G) for rs10067427 has risk to develop NAFLD?

Everyone has a risk of developing everything. But that one is almost certainly irrelevant to NAFLD. It was probably included in a study in NAFLD, but is never mentioned, which indicates it had no correlation with NAFLD. It's also very common and not on or anywhere near a gene.

See here : http://www.snpedia.com/index.php/Rs10067427

SNPedia is not a good source of information. http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=rs10067427 is a much better starting point.

 

[mariovitali]

@Valentijn

Hmm ok Thanks. I see no other way than having to read about GWAS Statistical analysis metthods to understand what is going on and what all these numbers mean properly.

 

[Gondwanaland]

IMHO NAFLD can be induced by high carb diet and/or meds in anyone.

 

[mariovitali]

Just wanted to tell you that i am back on being myself. No Symptoms whatsoever.


TUDCA and Choline may have a synergistic effect.


My current regimen is as follows :


08:00 : FMN, Dibencozide, Biotin, Metafolin
10:00 Choline, Inositol
<White Beans for Molybdenum, Banana for Potassium - until my supplements arrive>
12:00 TUDCA, P5P, Selenium
16:00 Choline, Inositol, Vitamin C
20:00 Choline, Inositol, Selenium
24:00 TUDCA


So TUDCA + Choline stays, i think the next one to go is Inositol.

FYI : The Choline i take is Alpha-GPC


I will keep you all posted.

 

[jump44]

Just wanted to tell you that i am back on being myself. No Symptoms whatsoever.


TUDCA and Choline may have a synergistic effect.


My current regimen is as follows :


08:00 : FMN, Dibencozide, Biotin, Metafolin
10:00 Choline, Inositol
<White Beans for Molybdenum, Banana for Potassium>
12:00 TUDCA, P5P, Selenium
16:00 Choline, Inositol, Vitamin C
20:00 Choline, Inositol, Selenium
24:00 TUDCA


So TUDCA + Choline stays, i think the next one to go is Inositol.

FYI : The Choline i take is Alpha-GPC


I will keep you all posted.

Good news @mariovitali ! Do you not take Taurine anymore? And whats the rational for taking alpha GPC as opposed to choline Bit-do you feel better w one form over the other?

 

[mariovitali]

@jump44

I switched because the Alpha-GPC arrived at my Mail ;-) I think it works better but perhaps this is just me. Taurine is out for now.


@Valentijn

This is the last question until i get myself educated for GWAS Analytics. Here is a snapshot from the R Code i use. I have the table ordered using my DNA data according to the Odds Ratio (column named "OR.or.Beta"- i know, not the best metric) but let's assume we keep this for now.

Note : The analysis uses HG38 data.

Could you make a comment for the rs numbers that i left visible in terms of their probability to be associated with the shown Disease/Trait?


Thanks again!

 

[Valentijn]

@mariovitali - Can you type out the rs numbers? They're too small to be certain about all of the digits in the image.

EDIT - Nevermind. It's letting me see the full image at a larger size now

 

[Valentijn]

rs1076540 does have research supporting the data in the table here - each C allele was found to be associated in a 4.8% increase in liver GGT levels, on average. Though I don't have the statistics background to know if their corrections for multiple comparisons (the entire genome) are sufficient.

But since that is the only study so far involving that SNP, I'd consider it to be pretty weak evidence. They probably need to replicate it, this time looking at only the 1,304 SNPs they found to have a significant impact, instead of all 3 billion SNPs on the human genome. And while there isn't much known about the gene it's on thus far, there's no other indication that it's involved with liver function at all.

In any case, the large majority of people have the "risky" type, so it's a bit silly to characterize it as being risky. It's more accurate to say that the rarer version is beneficial for the lucky few who have it. The 70% with CC are just normal, and CT and TT are better than normal.

Based on http://www.ncbi.nlm.nih.gov/pubmed/21612516 , it's actually the minor allele of rs10491334 (T) which has been found to be correlated to reduced longevity, and reduced levels of CAMKIV when homozygous (TT).

 

[mariovitali]

rs1076540 does have research supporting the data in the table here - each C allele was found to be associated in a 4.8% increase in liver GGT levels, on average. Though I don't have the statistics background to know if their corrections for multiple comparisons (the entire genome) are sufficient.

But since that is the only study so far involving that SNP, I'd consider it to be pretty weak evidence. They probably need to replicate it, this time looking at only the 1,304 SNPs they found to have a significant impact, instead of all 3 billion SNPs on the human genome. And while there isn't much known about the gene it's on thus far, there's no other indication that it's involved with liver function at all.

In any case, the large majority of people have the "risky" type, so it's a bit silly to characterize it as being risky. It's more accurate to say that the rarer version is beneficial for the lucky few who have it. The 70% with CC are just normal, and CT and TT are better than normal.

Based on http://www.ncbi.nlm.nih.gov/pubmed/21612516 , it's actually the minor allele of rs10491334 (T) which has been found to be correlated to reduced longevity, and reduced levels of CAMKIV when homozygous (TT).

I see. So the software i am using will be listing the 'risky' allele on this specific gene (rs10491334) towards the top of the table (since it is ordered by Odds Ratio) for most of the people (the unlucky ones that is).

The Big Question is : Is there a way with which informed hypotheses can be performed? I've read that Machine Learning methods are used that make the selection of the most relevant SNPs (aka "Feature Selection") in order to better classify Normal vs Non-Normal (=with Disease) individuals.

The "multiple comparisons" issue is well known for such a problem : Bonferroni correction is most likely not enough, this is a very tough nut to crack.

Nevertheless Thank you. I have so much reading to do...


The R code is here :

rm(list=ls())

library(gwascat)
d <- read.table("path_to_your_genome.txt", sep="\t", header=FALSE,colClasses=c("character", "character", "numeric", "character"),col.names=c("rsid", "chrom", "position", "genotype"))


tmp <- d$chrom
d$chrom = ordered(d$chrom, levels=c(seq(1, 22), "X", "Y", "MT"))
## It's never a bad idea to check your work
stopifnot(all(as.character(tmp) == as.character(d$chrom)))





data("gwrngs38")


gwrngs.emd <- as.data.frame(elementMetadata(gwrngs38))
dm <- merge(d, gwrngs.emd, by.x="rsid", by.y="SNPs")


risk.alleles <- gsub("[^\\-]*-([ATCG?])", "\\1", dm$Strongest.SNP.Risk.Allele)
i.have.risk <- mapply(function(risk, mine) {risk %in% unlist(strsplit(mine, ""))}, risk.alleles, dm$genotype)
dm$i.have.risk <- i.have.risk


my.risk <- dm[dm$i.have.risk, ]
rel.cols <- c(colnames(d), "Disease.Trait", "Risk.Allele.Frequency","p.Value","OR.or.beta", "X95..CI..text.","Strongest.SNP.Risk.Allele", "i.have.risk")

##NOTE Below : I am from Europe, therefore i chose "European" on the next line. If you are from US change to "American"

risks<-head(my.risk[grep("European", my.risk$Initial.Sample.Size), rel.cols], 300)

#risks<-head(my.risk[order(my.risk$Risk.Allele.Frequency), rel.cols], 50)

orderedrisks<-print(risks[order(risks[8],decreasing=T),])

write.csv(file='YOUR_DISK_PATH/riskalleles.csv', x=orderedrisks)

The code will analyze your 23andme data and create a csv file called 'riskalleles.csv' at a specified disk location. Just change YOUR_DISK_PATH on the last line of the code to the directory you wish to save the riskalleles.csv file.

You can download R from https://www.r-project.org/


Then you will have to install 'Bioconductor' : https://www.bioconductor.org/install/

In any case i would be happy to analyze the data of 10-15 members just to see what comes up..

 

[Violeta]

Just finished a new round of Analysis. We have two new Topics that appear on the top places, namely :

-NAD(P)H Dehydrogenase (quinone) 1 - (NQO1)
-Antioxidant Response Element (ARE)

View attachment 13102

See more


https://en.wikipedia.org/wiki/NAD(P)H_dehydrogenase_(quinone_1)


Here are the PubMed Topics under consideration :

NAD and NADH in the Kreb's cycle.

The name of this metabolic pathway is derived from citric acid (a type oftricarboxylic acid) that is consumed and then regenerated by this sequence of reactions to complete the cycle. In addition, the cycle consumes acetate (in the form of acetyl-CoA) and water, reduces NAD+ to NADH, and produces carbon dioxide as a waste byproduct. The NADH generated by the TCA cycle is fed into the oxidative phosphorylation (electron transport) pathway. The net result of these two closely linked pathways is the oxidation of nutrients to produce usable chemical energy in the form of ATP

 

[jump44]

So I went and bought standalone choline bit product twinlab 300mg yesterday. I wanted to give it a shot on its own over concerns with inositol and a test lowering possibility(I had bought a cheap inositol/choline combo product last week). The combo product had some nice effects on me. Anyways after taking 300mg of the choline last night i within an hour had a nasty headache, my sinus pressure also went way up. I went to bed at about 11 and had some really wild dreams. ANyway today has been plain miserable. I took my dog for a walk this am and all my bones hurt and I had to go get some caffeine a few minutes ago just to try and wipe this horrid fog and fatigue from my brain and body. Idk what to take away from this but just thought Id post as we are all sharing our experiences and this is a bit frustrating to say the least. My reaction was so bad that I dont even want to try the choline again. Very very odd considering the choline/inositol wasnt really harmful to me at all. There are really no other confounding variables as I didnt drink any alcohol or anything and didnt eat any of my "triggers".

Edit: THere was a 5-10 degree weather change(cooler) in the last day. I know mario hypothesized weather changes as a cause. However for me usually cooler weather is much better on my system, I cant rule it out as a possibility however with symproms appearing shortly after the choline intake I am pretty sure thats what it was.

 

[mariovitali]

@jump44

I would suggest that you switch back to what was working for you. I have seen no Testosterone-lowering effect of Inositol apart from PCOS.

-I would then try again at another time -say after 10 days- with a lower dosage -say half- of plain choline.

Is the type of choline different or is it the same Choline type in both supplements?

 

[jump44]

@mariovitali

Both products contain choline Bitartate, the choline only product is twinlab brand and the choline/inositol is
vitamin shoppe brand. Really bizarre that the one without inositol would have this effect. I remember a few years back when I was in a bit better shape I took alpha gpc and it worked pretty well for me, but when I tried it again last year it made me very fatigued. I will go back to the choline/inositol for the time being at a low dosage.

 

[mariovitali]

@mariovitali

Both products contain choline Bitartate, the choline only product is twinlab brand and the choline/inositol is
vitamin shoppe brand. Really bizarre that the one without inositol would have this effect. I remember a few years back when I was in a bit better shape I took alpha gpc and it worked pretty well for me, but when I tried it again last year it made me very fatigued. I will go back to the choline/inositol for the time being at a low dosage.

If i am not mistaken, you stopped TUDCA, is this correct?

 

[jump44]

If i am not mistaken, you stopped TUDCA, is this correct?

I had stopped it for a couple days last week due to an IBS type flare-up, however I restarted on saturday with no ill effects.

 

[mariovitali]

I had stopped it for a couple days last week due to an IBS type flare-up, however I restarted on saturday with no ill effects.

OK, could you PM me with the following info ?

-How many days you are on the regimen
-All supplements you are taking at the moment
-Symptoms
-How CFS started (EBV, Finasteride, without cause etc)


Thanks!

 

[skwag]

This paper has me a little concerned. It is only a rat study, though.


Urolithiasis in Rats Consuming a dl Bitartrate Form of Choline in a Purified Diet

Urolithiasis is a significant clinical problem in human and
veterinary medicine (2, 3, 19, 27, 28, 37), but the role of dietary
racemic bitartaric acid in this disease is only now becoming
appreciated.Levotartaric acid is a natural and soluble form found
in many foods and certain wines. This l isomer is excreted by
the kidney and appears to be biologically inert, but the racemic
version (dl) accumulates in the kidney and induces structural
changes consistent with crystalluria, a precursor of urolithiasis
(4, 6, 10). As evidenced in the outbreak described here, racemic
bitartaric acid is a potent inducer of urolithiasis. By the time
breeder (F0) rats in the present study were 28 months old and
their offspring (F1 rats) were 16 to 19 months old, the mortality
rate was nearly 30%.

The racemic bitartrate appears to be slightly cheaper and thus more likely to be in supplements, so we might worry that any given choline bitartrate supplement is actually choline DL bitartrate. It might be wise to verify with the manufacturer which form is used. The non-racemic form, chloine L bitatrate is available. For example here. The same company also sells the DL-bitartrate form, which appears to be much more popular.

I have not been able to find any information about human consumption of racemic bitartrate, good or bad. I feel like I'm missing something because the DL bitartrate is commonly sold and we don't hear about any kidney issues. If anyone can clarify the situation, please do.