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Glucocorticoid receptor polymorphisms and haplotypes associated with CFS.

Discussion in 'Adrenal Dysfunction' started by Ema, May 28, 2014.

  1. Ema

    Ema Senior Member

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    Interesting...

    Genes Brain Behav. 2007 Mar;6(2):167-76.
    Glucocorticoid receptor polymorphisms and haplotypes associated with chronic fatigue syndrome.
    Rajeevan MS1, Smith AK, Dimulescu I, Unger ER, Vernon SD, Heim C, Reeves WC.
    Author information

    Abstract
    Chronic fatigue syndrome (CFS) is a significant public health problem of unknown etiology, the pathophysiology has not been elucidated, and there are no characteristic physical signs or laboratory abnormalities. Some studies have indicated an association of CFS with deregulation of immune functions and hypothalamic-pituitary-adrenal (HPA) axis activity.

    In this study, we examined the association of sequence variations in the glucocorticoid receptor gene (NR3C1) with CFS because NR3C1 is a major effector of the HPA axis.

    There were 137 study participants (40 with CFS, 55 with insufficient symptoms or fatigue, termed as ISF, and 42 non-fatigued controls) who were clinically evaluated and identified from the general population of Wichita, KS.

    Nine single nucleotide polymorphisms (SNPs) in NR3C1 were tested for association of polymorphisms and haplotypes with CFS.

    We observed an association of multiple SNPs with chronic fatigue compared to non-fatigued (NF) subjects (P < 0.05) and found similar associations with quantitative assessments of functional impairment (by the SF-36), with fatigue (by the Multidimensional Fatigue Inventory) and with symptoms (assessed by the Centers for Disease Control Symptom Inventory).

    Subjects homozygous for the major allele of all associated SNPs were at increased risk for CFS with odds ratios ranging from 2.61 (CI 1.05-6.45) to 3.00 (CI 1.12-8.05). Five SNPs, covering a region of approximately 80 kb, demonstrated high linkage disequilibrium (LD) in CFS, but LD gradually declined in ISF to NF subjects. Furthermore, haplotype analysis of the region in LD identified two associated haplotypes with opposite alleles: one protective and the other conferring risk of CFS.

    These results demonstrate NR3C1 as a potential mediator of chronic fatigue, and implicate variations in the 5' region of NR3C1 as a possible mechanism through which the alterations in HPA axis regulation and behavioural characteristics of CFS may manifest.
     
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  2. Valentijn

    Valentijn Activity Level: 3

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    There's been other studies showing an abnormal increase in NR3C1 expression in properly defined ME patients after exertion as well.

    It's also a gene where ME patients had a decent number of abnormalities, when I glanced through it a while back. I should take a more in-depth look soon, and compare it to non-patients.
     
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  3. bertiedog

    bertiedog Senior Member

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    Thanks Ema. Presumably this would stop cortisol being produced in sufficient amounts for normal activities? This is something I have felt since around 1975 when I had a possible pituitary issue (severe blood loss following childbirth) and I often wonder if I had a double whammy, the problem with the pituitary plus later on I stopped producing sufficient cortisol after 2 weeks of flu from which I found it hard to recover and was never the same after. This all ended up with me needing replacement steroid since 2002.

    When I weaned myself off them in 2005/6 I ended up with 2 almost crises after severe bouts of diahorrea and vomittng but since being on the steroids I haven't had anymore crises even when I had the Norovirus this year.

    Pam
     
  4. Helen

    Helen Senior Member

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    Thanks @Ema and @Valentijn.
    Valentinj, could you please guide us how to browse our 23andme data to check for abnormalities? Would be of great help.
     
  5. Valentijn

    Valentijn Activity Level: 3

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    Here's a chart for the data from 12 ME patients (P1 - P12) and 12 controls (C1 - C12). Purple is less than 1% prevalence, red is 1 - 2.5%, orange is 2.5 - 5%, and yellow is 5-10%. SNPs for which there is some research listed are italicized, bolded, and underlined. Missense mutations are listed in red.

    NR3C1.gif

    So both groups are about the same for more common orange and yellow rare genotypes, but we have a helluva lot more of the rarest ones. I haven't looked at any of the research yet (though I should, since I'm P6), so no idea if any of it is potentially accountable for any dysfunctions we're having.

    Here's a text list of the SNPs, the rare allele, and any equivalent SNPs which also have research involving them:
    rs6198 - C
    rs10482714 - T
    rs10482704 - A
    rs10482682 - T
    rs6188 - A ( rs852977 rs860457 rs258750 rs258813 rs10052957 )
    rs33389 - T (rs860458 rs6196 rs2918419 )
    rs10482653 - A
    rs4912650 - G
    rs10482642 - C
    rs10042042 - A
    rs2963155 - G
    rs10515522 - C
    i5900005 - C ( rs56149945 )
    rs6190 - T
    rs6865292 - C
    rs4244032 - G
    rs13182800 - T
    rs12655166 - C
     
    Last edited: May 29, 2014
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  6. Helen

    Helen Senior Member

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    @Valentijn
    Great job! Thank you for the presentation. Do you know if P1 has symptoms related to the polymorphisms?
     
  7. Ema

    Ema Senior Member

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    rs1866388
    rs2918419
    rs860458
    rs6188

    These seem to be the ones that they found significance for in the study...though I haven't read the whole thing yet.
     
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  8. Ema

    Ema Senior Member

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    I don't think the study says how exactly the HPA axis is affected...it could presumably be over-production of cortisol, underproduction, or some other sort of dysregulation like cortisol resistance.
     
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  9. Ema

    Ema Senior Member

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    The paper can be found in the appropriate location.
     
  10. Ema

    Ema Senior Member

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    @stridor, thought you might want to look at your results in the context of this thread as well.

    I assume that positive means heterozygous for the risk allele?

    Nutrahacker results

    Cortisol receptor site.
    NR3C1

    rs2918419 ++
    rs860458 ++
    rs852997 ++
    rs6188 ++
    rs6198 ++
    rs1866388 ++
    rs258750 ++

    Corticotropin Releasing Hormone receptor
    CRHR1

    rs173365 ++
    rs7209426 +-
    rs110402 +-
    rs242924 +-
    CRHR2 rs2267710 +-
    rs2284217 +-
     
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  11. Sea

    Sea Senior Member

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    @Valentijn i5900005 if the MAF of 0.008 is correct should be purple not red. Interesting that there are 3 of us with this extremely rare one
     
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  12. Valentijn

    Valentijn Activity Level: 3

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    rs1866388 and rs6188 seem to be essentially the same, as do rs860458 and rs2918419.

    For rs6188/rs1866388 we have 6 "A" alleles (25%) compared to 4 for controls (17%).

    For rs860458/rs2918419 we have 3 "T" alleles (13%) compared to 2 for controls (8.3%).

    So not a big difference in prevalence of those specifically, though all the homozygous versions are on our side of the chart.
     
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  13. Valentijn

    Valentijn Activity Level: 3

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    It would be purple if homozygous, but heterozygous prevalence is 1.5872.
     
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  14. Snow Leopard

    Snow Leopard Senior Member

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    The overall association in this study was weak and it wasn't really found in other exploratory gene studies, I think it is just a coincidence personally.
     
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  15. Valentijn

    Valentijn Activity Level: 3

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    They also combine people with CFS and "fatigue" to compare to controls, since the p-values are too low otherwise and there's no significant results when comparing just the CFS bunch to controls. And even then, the p-values are pretty marginal - none at 0.01 or under.

    They're saying that CF patients have more:
    rs1866388 "A"
    rs2918419 "T"
    rs860458 "G"
    rs6188 "C"

    So their results in CF patients are all the opposite of those seen in our ME patients. Basically they're saying that CF patients have more of the common alleles, which is generally pretty useless, since most non-patients have them too.
     
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  16. stridor

    stridor Senior Member

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    @Ema
    Thank-you for bringing my attention to this site.

    First an observation - I have 6 of the SNPs mentioned plus a 7th that apparently wasn't considered in 2004, but it's also a NR3C1 glucocorticoid receptor.

    Then a comment. I think that ME is heterogeneous in terms of triggers and drivers. I believe that mine was triggered by mercury but driven by methylation problems and adrenals. I do not have Lyme or other chronic infections that I know of though I have never been tested. I did have Q-fever when I was 21 or so.

    Looking at the panel in this study, I am guessing that some people had more adrenal problems than others. I think that it would have been interesting although skewed, had they only used people who were taking cortef and the like.

    There are other factors that need to be considered as well, including the other panel above in Ema's call out to me. CRHR1 and 2 and others I suspect have a roll to play. Problems at the hypothalamus/pituitary making a weak call to the adrenals which have been damaged by mercury, which release too little cortisol given the condition of the receptors. Or something like that (?)

    Finally a question. There is one thing that I do not understand and that is prevalence. How can the "expected" allele be 15 %? I have SNPS where the risk allele ++ is 80% of the population. At first I thought that it was 'race' but when I go to SNPedia, I see that no, sometimes the expected is only found in a small minority in all populations.

    And another thing NutraHacker says that these SNPs are common. See below.

    Cortisol receptor site.
    NR3C1

    rs2918419 ++ 77%
    rs860458 ++ N/A
    rs852997 ++ 56%
    rs6188 ++ 54.7%
    rs6198 ++ 72%
    rs1866388 ++ 60%
    rs258750 ++ 56%

    In each case, the 'risk' allele is more common than the 'expected'. Not to be too glib but eventually wouldn't you stop expecting the other one :)
    It looks like the chart assigns a different prevalence. Why would that be? I only checked one but it appears NutraHacker is using SNPedia.

    I have turned my focus onto the adrenal problem. I'm not Addison's but I'm close. I have very little reserves but I have been getting some good advice on what it means to stress-dose. brad
     
  17. Valentijn

    Valentijn Activity Level: 3

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    Nutrahacker is a bit of hack job. They don't check the sources of their sources, and literally cut and paste stuff from random places on the internet. Hence their information often isn't presented in a coherent manner, and I wouldn't be surprised if they have a lot of inaccuracies.

    Some of my comments on PR, without citations, were copied word for word into the output of their reports. Which was a bit funny because I'm somewhat contrary regarding the Yasko opinions which they were parroting for other SNPs on the same genes.

    Basically they don't know what they're doing, but they think they've found a nice market to exploit.
     
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  18. stridor

    stridor Senior Member

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    @Valentijn Specific to this information on NR3C1, do you think that SNPedia is likely to be a reliable source. Unless these SNPs are linked (inherited together, which they could be as I am 7++ and my brother is 7 +-) candidate #1 must be one chance in several billion.
    I don't read statistics. Is there any other way of interpreting this discrepancy in SNP prevalence other than SNPedia is very wrong or this study is?
    NutraHacker, accurate or not, brought the glucocorticoid receptors to my attention and for that alone it was more than worth the price of admission :) brad
     
  19. Valentijn

    Valentijn Activity Level: 3

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    If you want proper statistics, dbSNP is the best place to look. SNPedia prevalence is either based of dbSNP, or the same source that dbSNP uses. I wouldn't trust SNPedia as much because it is a lot easier for someone to enter inaccurate information into it.

    There's no "one chance in a billion". It's basically two relevant SNPs, not 7, as most of them represent exactly the same information. And even those remaining two are fairly well linked together. Billions of people have exactly the same versions of those 7 SNPs as you do.
     
  20. stridor

    stridor Senior Member

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    @Valentijn There is no way I can ask the questions that I need to ask without sounding argumentative (or even more argumentative), but I need some answers in order to organize this new information. I will understand if you took licence in order to emphasize a point.

    a) there were 24 people in the table. Only one had 7 and another one had 4 SNPs. The remainder did not approach this.

    The authors were looking for subjects with strong symptoms as they were trying to prove an hypothesis. From these numbers surely the incidence of having 7 SNPs would be less than "billions"? Or am I missing something? I know that 24 is hardly an authoritative sampling size.

    b) what did the study mean that some of the SNPs showed a high linkage disequilibrium in CFS? Does this mean the SNPs are not linked? Looking at the table, and again aware of the sample size, These SNPs don't appear to be overly linked.

    c) do you happen to know how the " expected" allele becomes a fraction of the "variant"? It is driving me nuts that the expected is 15% across all races while the variant is 85%! I can't reconcile this.

    I have some serious adrenal things going on. I am wondering if I am approaching Addison's. I get BP drops after any activity and this is associated with some serious sitting and drooling.
    Working outside will drop me from 160/90 to 90/60 if I don't stress dose. (Then it is 112/68). With significant stress-dosing I worked 4 hours yesterday. Pretty active.

    I have a pile of adrenal SNPs and am trying to understand what is driving things. I am thinking that I should increase my base HC to 30 mg from 25 mg but my Dr is at the edge of his comfort zone. Having the same genetics as "billions" will not be enough to change things. Thanks for anything you can provide. brad
     

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