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Examination of Single Nucleotide Polymorphisms in Acetylcholine Receptors in Chronic Fatigue Syndrom

Discussion in 'Latest ME/CFS Research' started by Kati, May 27, 2015.

  1. Kati

    Kati Patient in training

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    From Sonya Marshall's group, Open access.
    http://www.la-press.com/examination...rphisms-in-acetylcholine-recept-article-a4862

    Abstract:

    Objective: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disorder characterized by debilitating fatigue accompanied by pain and impairments in memory, cognition, and concentration. Acetylcholine (ACh) has a plethora of roles in neuronal and neuromuscular transmission.

    There are two types of ACh receptors, muscarinic and nicotinic, comprising 17 different subunits of the nicotinic ACh receptor (nAChR) and five different subtypes of the muscarinic receptor (mAChR) that have been identified in humans.

    The purpose of this study was to determine the role of ACh receptor (nAChRs and mAChRs) single nucleotide polymorphisms (SNPs) in CFS/ME patients.


    Methods: One-hundred and fifteen CFS/ME patients (age = 48.68 ± 1.06 years) and 90 nonfatigued controls (age = 46.48 ± 1.22 years) participated in this study, where CFS/ME patients were defined according to the 1994 Center for Disease Prevention and Control (CDC) criteria.

    A total of 464 SNPs for nine mammalian ACh receptor genes (M1, M2, M3, M4, M5, alpha 2, 5, 7, and 10) were examined via the Agena Biosciences iPLEX Gold assay. Statistical analysis was performed using the PLINK analysis software.


    Results: Seventeen SNPs were significantly associated with CFS/ME patients compared with the controls. Nine of these SNPs were associated with mAChRM3 (rs4463655; P = 0.00281, rs589962; P = 0.00348, rs1072320; P = 0.00371, rs7543259; P = 0.00513, rs6661621; P = 0.00536 rs7520974; P = 0.0167, rs726169; P = 0.02349, rsrs6669810; P = 0.02361, rsrs6429157; P = 0.0375), while the remainder were associated with nAChR alpha 10 (rs2672211; P = 0.0107, rs2672214; P = 0.0108, rs2741868; P = 0.01185, rs2741870; P = 0.01281, rs2741862; P = 0.03043), alpha 5 (rs951266; P = 0.01153; rs7180002, P = 0.03682), and alpha 2 (rs2565048; P = 0.01403).


    Conclusion: The data from this pilot study suggest an association between ACh receptors, predominantly M3 and CFS. ACh receptor SNPs may contribute to the pathomechanism of CFS
     
    Last edited: May 27, 2015
  2. lansbergen

    lansbergen Senior Member

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    No assosiation with alfa7 found???
     
  3. alex3619

    alex3619 Senior Member

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    We have known since about 2000 that there was some kind of problem with the acetylcholine system, based on Vance Spence's work. Its the exact mechanism and its importance that remain ellusive.
     
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  4. Kati

    Kati Patient in training

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    i am impressed at the number of papers this group is putting out.

    Second comment is they have used the Fukuda criteria in this study and they still get significant results.
     
  5. Kati

    Kati Patient in training

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    Perhaps better technology will be in our favor?
     
  6. alex3619

    alex3619 Senior Member

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    One can hope so @Kati. Much of the technological revolution we see now came because computer technology invaded all the labs and homes in the 80s. What we really need though is well funded follow up studies. As always both funding and replication are likely to be an issue.
     
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  7. Research 1st

    Research 1st Severe ME, POTS & MCAS.

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    So from Kati's paper (thanks for posting Kati) of Sonya Marshall et al....

    .

    Makes me think of a good thread on Acetycholine on the forum in the past, which might tie in with the above statement?

    http://forums.phoenixrising.me/inde...cetylcholine-receptors-underpin-me-cfs.15692/

    And also maybe this study from Asia on CFS, from 2012. (Nice to see something outside of the US and Europe that is actively neuro/immune on ME CFS).

    Source: http://www.ncbi.nlm.nih.gov/pubmed/23240035.
    Reduction of [11C](+)3-MPB binding in brain of chronic fatigue syndrome with serum autoantibody against muscarinic cholinergic receptor.

    Severely affected PWME can report respiratory muscle breathing weakness (even from speaking, but without asthma), yet without the 'eye' sign of Myasthenia Gravis or other features. MG patients, like ME sufferers, also get worse as the day goes on, e.g. they run out of muscle energy to the extent they get very distressing symptoms.
     
    Last edited: May 27, 2015
  8. nandixon

    nandixon Senior Member

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    So that people can check their results, these are the 17 significant SNPs in the order given in the Abstract with the risk allele in parentheses; my 23andMe results are to the right (I was tested on the prior "v3" platform).

    (See Table 1 of the study for ranked order of significance based on p-value.)

    mAChRM3; gene=CHRM3
    rs4463655 N/A
    rs589962 (T)* CC -/-
    rs1072320 N/A
    rs7543259 (A) GG -/-
    rs6661621 N/A
    rs7520974 (A)* AA +/+
    rs726169 (T)* CT -/+
    rs6669810 N/A
    rs6429157 (G) AA -/-

    *Risk allele = major allele

    nAChR alpha 10; gene=CHRNA10
    rs2672211 N/A
    rs2672214 N/A
    rs2741868 N/A
    rs2741870 N/A
    rs2741862 N/A
    [Note: 23andMe gives only 1 SNP for this gene:
    rs2672215 (A) AA +/+,
    which is found in the Supplementary Table and has a p-value of 0.06523.]

    nAChR alpha 5; gene=CHRNA5
    rs951266 (A) AG +/-
    rs7180002 N/A

    nAChR alpha 2; gene=CHRNA2
    rs2565048 N/A
     
    Last edited: May 28, 2015
  9. Valentijn

    Valentijn The Diabolic Logic

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    It looks like they failed to correct for making hundreds of comparisons. Not too surprising, since their other recent SNP paper did the same thing, if I recall correctly. And it's still Fukuda patients, with no PEM mentioned. Some of the results with the lowest P values might be statistically significant, but if corrections were applied, their chosen P value of 0.05 would probably be far too high.
     
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  10. Hutan

    Hutan Senior Member

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    @nandixon Thanks for the list
    I think the alleles are just given as A1 and A2 with no commentary about risk.

    So, for the second SNP in the list,

    rs589962 (C) CC +/+ [p=0.00348]

    The A1 allele is (C). The frequency of that allele in the CFS patients is 24% and in the controls is 39%. So (C) is actually more common in the controls.

    So, in order for us to add weight to the paper's theory, we CFS patients should have the A2 allele (T) for that SNP.

    Do I have that right?
     
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  11. nandixon

    nandixon Senior Member

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    @Hutan, yes, I think you're right. I didn't read the table correctly. It looks like A1 is always the minor allele, and A2 is always the major, but the risk allele isn't always the minor allele, which isn't unusual, of course. I'll go back and edit my post in the next hour or two.

    ETA: I hopefully corrected it now.
     
    Last edited: May 28, 2015
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  12. Sidereal

    Sidereal Senior Member

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    I'm homozygous for a few on your list, @nandixon.
     
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  13. Gijs

    Gijs Senior Member

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    Very interesting! M3 receptor has a very important regulation in the whole body and can explain everthing what has been found in ME.
     
  14. Hutan

    Hutan Senior Member

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    I hope this formats ok - below are all the 23andme results for me and my son (both ME/CFS) that overlap with the study's significant SNPs.

    rs589962 (T) Hutan CT; Hutan's son CT
    rs7520974 (A) Hutan AG; Hutan's son AG
    rs726169 (T) Hutan TT; Hutan's son CT
    rs6429157 (G) Hutan AA; Hutan's son AA
    rs1594513 (T) Hutan TT; Hutan's son TT

    8/10 of our 10 SNPs have at least one of the required alleles.
    But most of those differences between allele frequency in CFS cases and controls look fairly small.
     
  15. nandixon

    nandixon Senior Member

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    @Hutan, I take it that you and your son were tested with 23andMe's more recent "v4" test version - since you're missing 2 of the 6 SNPs (out of 17) that I gave results for in post #8 above...?

    Also, is the additional SNP you gave, rs1594513, the only other SNP of the 23 given in Table 1 of the full paper that you have results for?

    I have that one and also one additional remaining one (rs2175886) from Table 1 that was tested on 23andMe's earlier v3 test version. Here are my results for the two:

    rs2175886 (C) CT +/-
    rs1594513 (A)* CC -/-

    *Risk allele = major allele

    So if I understand correctly, people tested on 23andMe's current test version will have results for 4 of the 17 significant SNPs found in the study, plus 1 additional one from Table 1, for a total of 5 SNPs.

    People tested on 23andMe's prior version should have 6 of 17, plus 2 additional ones, for a total of 8.
     
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  16. nandixon

    nandixon Senior Member

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    At least with respect to the statistics issue, the results should be okay based on @Mark's reporting here:

    (Bold is Mark's.)
     
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  17. Hutan

    Hutan Senior Member

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    Yes, v4

    Yes
     
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  18. Mark

    Mark Acting CEO

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    I intend to seek clarification from the researchers on the statistical details of the error correction in these papers, because based on conversations at IIME and here it's clear that there are quite a few people who are bemused as to how this error-correction can have taken place as claimed. I think we need to see the full workings to get to the bottom of this one. An important question because these findings could be an important part of the jigsaw, if they are replicable.
     
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  19. JaimeS

    JaimeS Senior Member

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    Ever find any clarification there? I'd like to cite this study with confidence, if possible.

    -J
     
  20. Mark

    Mark Acting CEO

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    No, I got side-tracked and never managed to follow up on this; similarly I never managed to write up the rest of my planned series of articles on the IiME conference. I did ask a question about this at IiME conference last year, and the response was (roughly) that Australia's foremost statistician had confirmed the statistical analysis. However, the details of the error-correction calculation remain unclear, it seems. I think it would be a really good idea for someone to follow up on this; @Simon would have the details about what still needs to be clarified. I find your attention to detail, in requiring clarification before citing this study with confidence, to be highly commendable.
     

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