Unfolded Protein Response and A Possible Treatment for CFS

[Bdeep86]

Thanks for all your contributions so far @mariovitali. I had a strange reaction to some of your supps I would like your opinion on. So I already had methylation supplements in place. As soon as I added TUDCA, ALPHA-GPC, and selenium around a week ago, I am experiencing increased fatigue, reduced appetite, nausea, darker urine and stools alternating between pale and yellow greasy looking. What do you think is the issue?

I also have genetic data through 23andme I could provide you if you want, but you'd have to tell me how to get it into a form that is useful to you. I only know how to get the raw data.

What form of selenium are you taking and at what doses.

 

[mariovitali]

@GreatGig

What i would do is to stop everything and check Liver function and Total Bile Acids.

 

[GreatGig]

I'm taking the l-selenomethionine in doses of 100mcg/day.

 

[mariovitali]

@all

After analyzing @GreatGig data here is what we have :

@Bdeep86 do you see the pattern?

CYP7A1 : Heterozygous
CYP8B1 : Not in chip
HSD3B7 : Homozygous
NR1H4 (=FXR Receptor, controls Bile Acid Levels) : Homozygous
SLCO1B1 : Homozygous (possibly associated with high Bilirubin and Gilbert's)


And now look at the chart (notice where CYP7A1,HSD3B7 are located in the pathway) :

http://forums.phoenixrising.me/inde...e-treatment-for-cfs.37244/page-73#post-699688

And add on top of that a Homozygous FXR Receptor.

NR1H4 (Nuclear Receptor Subfamily 1, Group H, Member 4) is a Protein Coding gene. Diseases associated with NR1H4 include intrahepatic cholestasis and atp8b1 deficiency. Among its related pathways are Metabolism and Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha). GO annotations related to this gene include transcription factor activity, sequence-specific DNA binding and receptor activity. An important paralog of this gene is NR1I2.

 

[douglasmich]

I have TUDCA the smell is horrible lol. Started taking 250mg today. I am 80kg and i have PFS. What dosage should i take? I hope it helps my terrible constipaiton

 

[Valentijn]

CYP7A1 : Heterozygous
CYP8B1 : Not in chip
HSD3B7 : Homozygous
NR1H4 (=FXR Receptor, controls Bile Acid Levels) : Homozygous
SLCO1B1 : Homozygous (possibly associated with high Bilirubin and Gilbert's)

Genes aren't heterozygous or homozygous. SNPs are. And most of the SNPs you have referred to on these genes in the past do not have any impact.

 

[Violeta]

CYP7A1provided by HGNC
Official Full Name
cytochrome P450 family 7 subfamily A member 1provided by HGNC
Primary source
HGNC:HGNC:2651
See related
Ensembl:ENSG00000167910; HPRD:00324; MIM:118455; Vega:OTTHUMG00000164301

Organism
Homo sapiens

Also known as
CP7A; CYP7; CYPVII
Summary
This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum membrane protein catalyzes the first reaction in the cholesterol catabolic pathway in the liver, which converts cholesterol to bile acids. This reaction is the rate limiting step and the major site of regulation of bile acid synthesis, which is the primary mechanism for the removal of cholesterol from the body. Polymorphisms in the promoter of this gene are associated with defects in bile acid synthesis. [provided by RefSeq, Feb 2010]


http://www.ncbi.nlm.nih.gov/gene/1581

 

[mariovitali]

Genes aren't heterozygous or homozygous. SNPs are. And most of the SNPs you have referred to on these genes in the past do not have any impact.

Being more specific would be helpful :

-Which genes specifically have no impact?
-How much confident are you in saying that they have no impact? Can you post References?

 

[Undisclosed]

Being more specific would be helpful :

-Which genes specifically have no impact?
-How much confident are you in saying that they have no impact? Can you post References?

mariovitali -- I think you are misunderstanding what Valentijn said. She didn't say 'genes' have no impact because they very much do. She said 'and most of the SNPs you have referred to on these genes in the past do not have any impact' which is referring to snp's.

 

[Bdeep86]

I'm taking the l-selenomethionine in doses of 100mcg/day.

I would drop this. This is actually a horrible form of selenium and your mostly getting methionine from it. I spoke with a mineral/nutirion expert a few months ago and they said to avoid this.

 

[Violeta]

I would drop this. This is actually a horrible form of selenium and your mostly getting methionine from it. I spoke with a mineral/nutirion expert a few months ago and they said to avoid this.

What is a good type.

 

[Bdeep86]

@all

After analyzing @GreatGig data here is what we have :

@Bdeep86 do you see the pattern?

CYP7A1 : Heterozygous
CYP8B1 : Not in chip
HSD3B7 : Homozygous
NR1H4 (=FXR Receptor, controls Bile Acid Levels) : Homozygous
SLCO1B1 : Homozygous (possibly associated with high Bilirubin and Gilbert's)


And now look at the chart (notice where CYP7A1,HSD3B7 are located in the pathway) :

http://forums.phoenixrising.me/inde...e-treatment-for-cfs.37244/page-73#post-699688

And add on top of that a Homozygous FXR Receptor.

Yep, I think CYP7A1 is something we are going to see a lot of to be honest. The others as well.

 

[Valentijn]

-Which genes specifically have no impact?

Genes have an impact obviously, since they produce proteins. But most SNPs on genes do not impact the form or amount of the proteins produced.

-How much confident are you in saying that they have no impact? Can you post References?

Most SNPs have no impact. Thus most SNPs which have not been researched also will turn out to have no impact.
https://ghr.nlm.nih.gov/handbook/genomicresearch/snp : "Most SNPs have no effect on health or development."
https://www.23andme.com/gen101/snps/ : "... most SNPs seem to lead to no observable differences between people at all."

Until research shows otherwise, it is most likely that each SNP is not relevant. Guessing that each rarer SNP is relevant, as you seem to be doing, will result in a mistaken conclusion for the large majority of SNPs. And even then it cannot possibly predicted whether any SNP is an upregulation or a downregulation, making any resulting recommendations potentially very inappropriate or even harmful by acting to exacerbate an existing problem.

Unfortunately that means we have to rely on the little research available for the SNPs on those genes which are tested by 23andMe. We have no choice but to assume that the rest do nothing until proven otherwise in rigorously conducted research, and guessing is completely futile at this point.

 

[mariovitali]

@Valentijn

Unfortunately your perception of what Research is, is not compatible to what i think Research is. I also add the element of a "Hypothesis".

So Hypothesis =>Research=> Accept/Reject Hypothesis.

After all, Research has something called "Hypothesis Testing"....right?

Probably you are thinking that the Hypothesis being discussed here is flawed because it is based on SNPs that have no impact.

Again, until a group of researchers looks into my Hypothesis looking into the combination of SNPs and NOT individual SNPs and make proper Experimentation my Hypothesis cannot be Rejected a priori.

In other words i am saying : "Here is my Hypothesis, accept/reject this Hypothesis with a pre-specified level of confidence".

Could you also tell me which SNPs and rs# of CYP7A1 do not have an impact to Health and which do? Or there are no SNPs (according to your opinion) to CYP7A1 Gene that cause ANY problems?

 

[Valentijn]

After all, Research has something called "Hypothesis Testing"....right?

There is already a great deal of evidence that your hypothesis (of all SNPs on these genes being relevant) is completely wrong. Why create a hypothesis which has already been shown to not be true? How does anyone gain from that?

Your hypothesis relies on the assumption that the entire field of genetics has gotten the science completely wrong. That makes it an extremely implausible hypothesis, especially while you completely fail to explain in a scientific context (beyond "anything is possible") why you believe it is wrong.

Could you also tell me which SNPs and rs# of CYP7A1 do not have an impact to Health and which do? Or there are no SNPs (according to your opinion) to CYP7A1 Gene that cause ANY problems?

I'm sure there are SNPs on CYP7A1 which cause minor problems. And determining which ones they are will take weeks or months of reading the existing research. It's not a project I am at all interested in undertaking.

But you can do the same work yourself, if you really want to.

 

[mariovitali]

@Valentijn

I see, so what is "the great deal of evidence" you are referring to exactly? The fact that the SNPs being discussed have probably no Impact?

If yes, how come an algorithm is able to predict Fast vs Slow Acetylators by having as input a number of NAT2 Genes? This *could* mean (notice how careful i am!) that the combination of SNPs leads to a specific phenotype



http://nat2pred.rit.albany.edu/

I have asked you this question many times, please answer that so i may understand your way of thinking.

 

[mariovitali]

I'm sure there are SNPs on CYP7A1 which cause minor problems. And determining which ones they are will take weeks or months of reading the existing research. It's not a project I am at all interested in undertaking.
But you can do the same work yourself, if you really want to.

In my opinion, Primary Biliary Cirrhosis is not a "Minor problem". Do you think it is a Minor problem @Valentijn ?

Association of genes involved in bile acid synthesis with the progression of primary biliary cirrhosis in Japanese patients.
Inamine T1, Higa S, Noguchi F, Kondo S, Omagari K, Yatsuhashi H, Tsukamoto K, Nakamura M.
Author information

Abstract
BACKGROUND:
Patients with primary biliary cirrhosis (PBC) exhibit a variety of clinical manifestations and patterns of disease progression. The aim of this study was to identify genetic determinants of PBC progression.

METHODS:
A total of 52 tag single nucleotide polymorphisms (SNPs) of 11 candidate genes involved in regulating bile acid synthesis were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, -high resolution melting curve analysis, or -direct DNA sequencing in 315 Japanese patients with PBC.

RESULTS:
In this study, four tag SNPs of CYP7A1 (rs1457043, rs8192870, rs3808607, and rs3824260), two tag SNPs of HNF4A (rs6017340 and 6031587), and one SNP of PPARGC1A (rs8192678) showed a significant association with PBC progression. In addition, a dual luciferase assay revealed that the polymorphism of rs3808607 in CYP7A1 altered the expression of CYP7A1 in HepG2. Specifically, the CYP7A1 promoter carrying the risk G allele for PBC progression induced higher expression of CYP7A1 under both the normal and cholestatic conditions in vitro as compared to another promoter carrying the non-risk T allele.

CONCLUSION:
These results suggested that the genetic variants of CYP7A1 and its transcriptional activators (HNF4A and PPARGC1A) may activate bile acid synthesis, resulting in the accumulation of bile acids in hepatocytes and eventually leading to the predisposition to PBC progression. Thus, the regulation of CYP7A1 expression may represent an attractive therapeutic target for cholestatic liver diseases including PBC.

Of course association does not mean causation...but one cannot make claims of "minor problems" without looking at Research. Right?

In my way of thinking, your way of Thinking is Dangerous and i believe that i presented the reason why. I have nothing with you By the way and if i said things that were personal i do apologise and will make sure it does not happen again.

But....i do believe that your way of thinking is dangerous.

I also have added red fonts on two rs# that are being discussed in this Thread for your Reference.

So i am all yours for a fruitful conversation based on what i have presented above

 

[Valentijn]

I see, so what is "the great deal of evidence" you are referring to exactly? The fact that the SNPs being discussed have probably no Impact?

The quotes from the sources I listed above, that most SNPs do not have impact. And those conclusions are based on thousands of research studies conducted over several decades. Read some of those SNP studies and you will see it every time - a couple SNPs on a gene show a correlation, and dozens or even hundreds more that were tested don't.

If yes, how come an algorithm is able to predict Fast vs Slow Acetylators by having as input a number of NAT2 Genes? This *could* mean (notice how careful i am!) that the combination of SNPs leads to a specific phenotype

I think you're referring to a haplotype, not an algorithm. They're not really "predicting" that the SNPs themselves are relevant together. They've already found a correlation between gene function and a series of specific alleles or genotypes among multiple SNPs by conducting research.

But again, that is something which is determined by conducting rigorous research, and such haplotypes are not found very often, even though researchers are looking for them. They are definitely not just guessing that "this SNP looks cool, I bet it does X. And if we combine it with this other SNP, I bet it does Y!" Instead they ran large trials looking at the activity of the protein created, and independent researchers looked for the same correlations and were able to verify them. This is very different from guessing or even predicting.

In my opinion, Primary Biliary Cirrhosis is not a "Minor problem". Do you think it is a Minor problem @Valentijn ?

The contribution of the SNPs is minor. I think this is another case where you are failing to understand the basic concepts and terminology involving genetics in general, and this appears to be leading you to make incorrect assumptions about pretty much everything that is being explained to about the subject.

 

[mariovitali]

@Valentijn


-SVM is Machine Learning Algorithm that can also solve Classification problems (which is a Prediction problem)

-The website clearly talks about a "predictor".

-The research i posted is not about my Beliefs.

I will stop this conversation here so that others can decide for themselves which of the two ways of Thinking they prefer.

 

[Valentijn]

@mariovitali - I'm trying to think of a good way to explain the relationship between SNPs and disease. I'm not a teacher, so it's not something I'm any good at. But since you don't have a couple hours per week to spare for a proper free introductory course online, here's my attempt:

SNPs (or more specifically alleles) are the basis of genes. Typically there are hundreds or thousands of them on each gene. The gene creates a protein. If there is a major change in that protein, it might function differently. That can result in too much or too little of the protein, or the protein being too effective or ineffective at doing its job, or no protein being created at all. When the protein is badly malfunctioning, that is when disease can result.

SNPs --> gene --> protein --> disease.

So SNPs can result in disease, but you can't take a shortcut straight from SNP --> disease. The SNP will only cause disease if it fundamentally alters the protein. But most SNPs don't alter the proteins at all - and that's a very good thing, because they are made of nucleobases (A, C, G, T), where cytosine (C) is rather fond of spontaneously degrading (deaminating) into thymine (T). That degradation usually gets fixed, but often it doesn't. Luckily our DNA isn't so fragile as to have most minor changes causing disease, or any problems at all.

But there are places where the specific alleles are a lot more relevant. This can be in splicing sites (which are known about), and a different allele can cause exons to be skipped. But most of these alleles are in the exons themselves. These exons are clearly marked on various utilities like dbSNP. The alleles in the exons spell out the amino acids which are linked together to form proteins. Each group of three consecutive SNPs forms a "codon" which specifies the next amino acid to add to the protein, or the codon signals that the end of the protein has been reached and no more amino acids are to be added.

SNP --> codon --> amino acid --> protein structure --> disease.

But even in exons we cannot skip straight from having a different allele on a SNP to assuming there is an alteration in the protein structure, much less a resulting disease. Each codon specifies an amino acid, but they often are not very picky about it being completely precise. Much like in misspelling words, a slight variation in a codon is often still understood to create the correct amino acid. Most commonly, the third (final) allele in each codon can have 2 or 4 variations which result in creating the same amino acid. So it doesn't matter at all if a codon in an exon has "TCG" instead of "TCA", as they both result in serine being added to the protein, and the function is completely unchanged.

But even when a different amino acid is created by a codon, it often doesn't have a significant impact. Many amino acids are pretty similar to each other, and result in the protein having the same integrity and form as the more common version. So here there is a slightly different protein being made, but usually without any resulting disease or other significant impact. The actual problems arise in exons when:

1. the change is in an important region where the protein interacts (connects) with another protein
2. the new amino acid has very different behavior
3. there is a premature termination of the protein prior to the important parts of it, or
4. there is an inserted or deleted allele, resulting in a frame-shift, and the "reading" of the codons to create the amino acids gets completely garbled.

The impact of these changes can often be predicted without actual genetic research, due to what is known about the behavior of the amino acids, the importance of specific parts of the protein created, and even things like 3D modeling of the resulting protein. Though even then, it's essentially an educated guess.

Basically, it's not possible to guess that SNPs outside of exons are having any impact. We need proper research showing that those SNPs do or do not have an impact. If predicting is to be done, it's for the missense mutations (amino acid changes) or nonsense mutations (premature stops) in the exons, and there are valid ways in which to go about it. Some are simple, like the BLOSUM62 amino acid chart, and some programs evaluate dozens of factors regarding the amino acid, it's location, nearby amino acids, 3D modeling, etc. So this is also a far cry from guessing blindly.