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Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes in CFS

Discussion in 'Genetic Testing and SNPs' started by Beyond, Oct 18, 2013.

  1. Beyond

    Beyond 10% of discount in iHerb!--> PEZ915

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    http://www.ncbi.nlm.nih.gov/pubmed/16610957

    Abstract

    OBJECTIVE:
    This paper asks whether the presence of chronic fatigue syndrome (CFS) can be more accurately predicted from single nucleotide polymorphism (SNP) profiles than would occur by chance.
    METHODS:
    Specifically, given SNP profiles for 43 CFS patients, together with 58 controls, we used an enumerative search to identify an ensemble of conjunctive rules that predict whether a patient has CFS.
    RESULTS:
    The accuracy of the rules reached 76.3%, with the highest accuracy rules yielding 49 true negatives, 15 false negatives, 28 true positives and nine false positives (odds ratio [OR] 8.94, p < 0.0001). Analysis of the SNPs used most frequently in the overall ensemble of rules gave rise to a list of 'most important SNPs', which was not identical to the list of 'most differentiating SNPs' that one would calculate via studying each SNP independently. The top three genes containing the SNPs accounting for the highest accumulated importances were neuronal tryptophan hydroxylase (TPH2), catechol-O-methyltransferase (COMT) and nuclear receptor subfamily 3, group C, member 1 glucocorticoid receptor (NR3C1).
    CONCLUSION:
    The fact that only 28 out of several million possible SNPs predict whether a person has CFS with 76% accuracy indicates that CFS has a genetic component that may help to explain some aspects of the illness.

    And: http://www.ncbi.nlm.nih.gov/pubmed/16610949

    In my opinion MAO A and B homozigous polymorphisms are also significant in psychophysical illness (HPA axis). I have both! My plan for these two is high dose curcumin.

    Oh and I will add one that actually has "rs´s"! http://www.ncbi.nlm.nih.gov/pubmed/18079067

    23and have that one bugged, what luck. http://snpedia.com/index.php/Rs6311
  2. roxie60

    roxie60 Senior Member

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    What do you mean by 'bugged'? It shows up as TT for me i 23andMe so I presume this study is looking at the opposite strand...???? A=T G=C just a reminder.
    Beyond likes this.
  3. Beyond

    Beyond 10% of discount in iHerb!--> PEZ915

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    Thanks roxie. I am the one that is bugged! :D So, you have the homozigous mutation that they associate with CFS. I have it hetero. And other hetero and two homozigous (one unhealthy and the other normal) in the http://snpedia.com/index.php/HTR2A.

    http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031211

    " It is interesting to note that 12-week curcumin treatment strongly reduced the expression levels
    of these two serotonin receptors in the hippocampus (Htr2c) and cortex (Htr2a) of the aged rats,
    respectively (Table 2)."

    My main interest lays in substances and/or treatments that down or upregulate the expression of our mutations. This is CHINESE WORK as we would say in spanish but it is well worth it and interesting.
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  4. Snow Leopard

    Snow Leopard Senior Member

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    65% sensitivity is very poor and I believe most of the SNPs identified in this study are actually quite common in general and are unlikely to be directly associated with disease. I don't think much can be concluded from this study at all, unfortunately.

    Additional:
    It could be argued that the poor sensitivity and specificity were due to the flawed definition used for these patients (CDC Reeves 'empirical' criteria). My conclusion was based on this study alone. Rather than concluding that there is no genetic factor, I've just concluded that this study does not provide sufficient evidence that there is one.
    helen1 and Valentijn like this.
  5. Beyond

    Beyond 10% of discount in iHerb!--> PEZ915

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    Hey could you tell me where is that 65% sensivity? I couldnt find it. Whatever the case, those genes, enzymes, receptors and pathways having to do with the HPA axis are probably related with chronic fatigue.

    http://onlinelibrary.wiley.com/doi/10.1111/j.1601-183X.2006.00244.x/full
  6. Snow Leopard

    Snow Leopard Senior Member

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    28/43 x 100% = 65%

    http://en.wikipedia.org/wiki/Sensitivity_and_specificity

    Specificity is more complicated because it depends on what group you are comparing to.

    I read the aforementioned study a few years ago when I was investigating all the neuroendocrine studies and it didn't really make an impression on me at all with regards to clues.

    I don't believe the evidence, taken as a whole shows that the HPA axis is dysfunctional. The adrenal gland has been shown to work effectively in patients and the functioning overall has still shown to be quite robust. In my opinion, particularly after the recent gene expression studies by Light et al, is that the HPA axis is responding in a useful manner (broad anti-inflammatory response) against a background of unusually prolonged cellular oxidative stress and likely immunological dysregulation.
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  7. Beyond

    Beyond 10% of discount in iHerb!--> PEZ915

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    I really appreciate your deeper experience with scientific literature. In what I agree is in the oxidative stress and immunological dysregulation, but I still hold that some of us have what is known extraofficially as adrenal fatigue.

    If this adrenal fatigue has or not to do with failing HPA signals or what not I dont know, but the hypocortisolism in CFS patients is easy to witness as a common denominator. Studies back up the validity of saliva cortisol testing which is the one that shows this.
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  8. Valentijn

    Valentijn Activity Level: 3

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    According to the text, it looks like they're saying that (basically) these 4 SNPs together mean greater risk of CFS:
    TPH2 rs1386486 (A)
    NRC1 rs6196 (A)
    NR3C1 rs6188 (C)
    CRHR2 rs2284217 (A)

    I'm hetero for TPH2 and have the rather rare and protective homozygous versions of NRC1 and NR3C1. No call on the 4th. So basically, according to that I'm not at all likely to have CFS. :confused:

    This is clarified by looking at the definition used - the 2005 empirical version by Reeves. Basically at least a third of patients are guaranteed to have Major Depressive Disorder instead of ME/CFS. So basically this study is not of ME/CFS patients.

    So maybe it's really just saying that I have a reduced chance of MDD? :D
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  9. roxie60

    roxie60 Senior Member

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    What happened to the rs6311 identified above? Where does that fit in? I am TT on rs6311. I added my values in pink below. Valentijn, so what are you protective homozyg values?

  10. Valentijn

    Valentijn Activity Level: 3

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    Basically none of it matters. Due to the really bad cohort used, it wasn't an ME/CFS (or any other disease) study at all. But rs6311 doesn't look like it factored into any of their haplotypes.
  11. Beyond

    Beyond 10% of discount in iHerb!--> PEZ915

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    I guess that for some these genes might be related to the illness, and for others not. We would need a larger and more comprehensive genetic review of patients to draw more general and reliable conclusions.
  12. Beyond

    Beyond 10% of discount in iHerb!--> PEZ915

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    Getting to the "treatment part". Curcumin inhibits MAO A and B and reduces the activity of HTR2A.
    http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031211

    I will be taking it and investigating the other genes. I was mentally troubled (as so are my brothers and sister) long before any physical symptom so for me this is very very important. Of course, healing leaky gut goes first but curcumin helps with that as well so win-win!
  13. roxie60

    roxie60 Senior Member

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    I've heard positives about curcumin. Just never used it in cooking before, wonder if its usefulness is impacted if cooked (heat) with other food?
  14. Beyond

    Beyond 10% of discount in iHerb!--> PEZ915

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    Roxie curcumin is the active principle in turmeric, the food spice. Taking turmeric isnt the same as taking curcumin, because you cannot know the amount of curcumin in the specific turmeric you are taking and you would need to take a lot of turmeric (I have yet to research this but looks like that). http://www.ncbi.nlm.nih.gov/pubmed/17044766
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  15. Beyond

    Beyond 10% of discount in iHerb!--> PEZ915

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    This is where "CFS" overlaps with depression and fatigue sufferers. Remember the TPH2 gene that was found involved with chronic fatigue ? It seems the correct rs to look for is rs12229394. The risk allele is A and I have it homozigous. Good news is Bacopa Monnieri upregulates TPH2. I dont know if the mutation associated with fatigue and depression is an up or down regulation, but it looks like a downregulation.

    http://www.julkari.fi/bitstream/handle/10024/90870/URN_ISBN_978-952-245-651-9.pdf?sequence=1
  16. Valentijn

    Valentijn Activity Level: 3

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    The effect size is pretty small, and the association with "fatigue" is barely significant. The "risk" allele is also very common, present in between 20% and 50% of various populations. It's also not a missense or other significant type of mutation, so even less likely to have much impact, if any.

    They looked at at least 200 SNPs, so odds are good that statistically significant-looking false positives will turn up, especially if they didn't correct for that probability when determining p values.
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  17. Beyond

    Beyond 10% of discount in iHerb!--> PEZ915

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    Valentijin how do you know the percentage of people that has an allele? And the various rs´s inside one gene, how are they called? Variants?

    Regarding what you say, it might be, but the thing is these genes keep popping out in different genetic studies of CFS, depression and fatigue, so they must be involved for some. Maybe not any of the alleles I posted, maybe some, but for sure these genes are involved in the illness of some people.
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  18. Valentijn

    Valentijn Activity Level: 3

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  19. nandixon

    nandixon Senior Member

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    I'm also homozygous (AA) for rs12229394. If it's true that that SNP is associated with fatigue then I think the chances are greater that it's an up regulation rather than a down regulation. Typically, increased serotonin causes fatigue (deceased serotonin causes depression). According to HapMap CEU data (and also OpenSNP), about 7% of the Caucasian population is homozygous +/+ for that SNP.

    A good example of a SNP or haplotype that is known to cause an up-regulation in the TPH2 gene is rs7305115, which increases mRNA expression by up to 2.5x. I'm homozygous (AA, 17% CEU frequency) for that one and also have the most up-regulating haplotype (TAAGA), which is common, comprising rs2171363-rs4760815-rs7305115-rs6582078-rs9325202, and noted in this study:

    http://www.ncbi.nlm.nih.gov/pubmed/17453063/

    (Free full text pdf download here: http://www.readcube.com/articles/10.1038/sj.mp.4001923)
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  20. nandixon

    nandixon Senior Member

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    I think you're right. While it may not be that a defect in a serotonergic pathway is a cause of ME/ CFS, it might make matters worse for some subset of us.

    For myself, anything that increases serotonin, either directly or indirectly, exacerbates my fatigue. So possible treatments to explore might be a serotonin receptor antagonist like cyproheptadine (an antihistamine also used for serotonin syndrome), or maybe better, an actual tryptophan hydroxylase inhibitor like parachlorophenylalanine (PCPA, used in carcinoid syndrome). If someone is producing too much serotonin, then I'd think that both curcumin and Bacopa would tend to be bad.
    Beyond likes this.

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