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Genes in ME Convergent genomic studies identify association of GRIK2 & NPAS2 with CFS

Discussion in 'Latest ME/CFS Research' started by Legolas, Sep 13, 2011.

  1. Legolas

    Legolas

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    Convergent genomic studies identify association of GRIK2 andNPAS2 with Chronic Fatigue Syndrome------------------------------------------------------------
    Alicia K. Smith(a), Hong Fang(b), Toni Whistler(a), ElizabethR. Unger(a), Mangalathu S. Rajeevan(a,*)a Division of High-Consequence Pathogens and Pathology, Centersfor Disease Control and Prevention, Atlanta, Ga., andb Z-Tech Corporation, an ICF International Company at NCTR/Foodand Drug Administration, Jefferson, Ark., USA* Author Contacts - Mangalathu S. RajeevanDivision of High-Consequence Pathogens and PathologyCenters for Disease Control and Prevention, 1600 Clifton RoadAtlanta, GA 30333 (USA)Tel. +1 404 639 2931, E-Mail mor4@cdc.gov

    Abstract

    Background

    There is no consistent evidence of specific gene(s) or molecular pathways that contribute to the pathogenesis, therapeutic intervention or diagnosis of chronic fatigue syndrome (CFS). While multiple studies support a role for genetic variation in CFS, genome-wide efforts to identify associated loci remain unexplored. We employed a novel convergent functional genomics approach that incorporates the findings from single-nucleotide polymorphism (SNP) and mRNA expression studies to identify associations between CFS and novel candidate genes for further investigation.

    Methods

    We evaluated 116,204 SNPs in 40 CFS and 40 nonfatigued control subjects along with mRNA expression of 20,160 genes in a subset of these subjects (35 CFS subjects and 27 controls) derived from a population-based study. ResultsSixty-five SNPs were nominally associated with CFS (p < 0.001), and 165 genes were differentially expressed (>=4-fold; p=<0.05) in peripheral blood mononuclear cells of CFS subjects. Two genes, glutamate receptor, ionotropic, kinase 2 (GRIK2) and neuronal PAS domain protein 2 (NPAS2), were identified by both SNP and gene expression analyses. Subjects with the G allele of rs2247215 (GRIK2) were more likely to have CFS (p=0.0005), and CFS subjects showed decreased GRIK2 expression (10-fold; p=0.015). Subjects with the T allele of rs356653 (NPAS2) were more likely to have CFS (p=0.0007), and NPAS2 expression was increased (10-fold; p=0.027) in those with CFS.

    Conclusion

    Using an integrated genomic strategy, this study suggests a possible role for genes involved in glutamatergic neurotransmission and circadian rhythm in CFS and supports further study of novel candidate genes in independent populations of CFS subjects.

    Key Words: Chronic fatigue syndrome - Genome-wide association - Gene expression - GRIK2 - NPAS2 - Glutamatergic neurotransmission - Circadian rhythm - Orexin signaling

    View attachment Convergent genomic studies identify association of GRIK2 andNPAS2 with Chronic Fatigue Syndrome.pdf
     
  2. Legolas

    Legolas

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    The above study suggests the glutamatergic neurotransmission playing a role in the pathogenesis of ME.
    If you keep this in mind and read the article below it's not hard to imagine immunoexcitotoxicity may explain ME for a big part.

    http://www.surgicalneurologyint.com...2;issue=1;spage=107;epage=107;aulast=Blaylock


    greatz

    Legolas

    (ps; I'm not English speaking by nature so my apologies for possible language mistakes)
     
  3. oceanblue

    oceanblue Senior Member

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    Leaving aside the fact that this use the largely pointless (to understanding cfs/me) empiric criteria, as I understand things you would need at least 1,000 patients (as opposed to 40) to have a prayer of finding meaningful correlations.

    With 116,000 SNPs you are likely to pick up a lot of seemingly significant associations just by chance. Rigorous gene-wide studies also use a 2-stage approach: stage 1, exploratory, identifies candidate snps. Stage 2, confirmatory, checks if the SNPs identified in stage 1 are also significantly associated with cfs in stage 2 (this helps exlcude snps that appear highly significant, but have been picked up just by chance).
     
  4. Legolas

    Legolas

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    I agree with the selection criteria criticism. But nonetheless it still will contain at least a portion of ME patients (I guess...)
    Since financial investment in ME is scarce these are the things we'll have to do it with.
    I guess one might consider it as a kind of stage one SNP investigation. If other researchers (using decent criteria), for example with limited financial resources want to do some genetic research they can use the SNP's found here (instead of going over the full 116 000 again and paying the full price) and see if there really is a correlation. If they find the same results than this is a valuable study, if they can't,well .....
     
  5. Valentijn

    Valentijn Activity Level: 3

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    Excess glutamate is possibly a result of inability to produce glutathione. Glutamate is one of the the three components of glutathione, and if one of the others is missing (probably cysteine), there's extra glutamate (and glycine) in the body that's not being used.

    I tested very high for both glutamate and glycine, and treating the glutamate has resolved my NMH symptoms almost completely.
     
  6. ukxmrv

    ukxmrv Senior Member

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    Legolas,

    The concern over the poor empiric criteria is that any people with ME will be few and just swallowed up by the others included. We don't have to take this quietly and can complain / campaign to have valuable funds spent on more robust criteria.

    I hear what you are saying about using this as a start and appreciate this it could save time for anyone wanting to do the same for PWME. It could also mean that specific genes that identify this group will be missed again. It's a hard one but if they had done the research on a properly defined group of patients we would not be in this quandary of not knowing.

    http://www.ipetitions.com/petition/empirical_defn_and_cfs_research/
     
  7. determined

    determined Senior Member

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    I saw this yesterday and looked up my SNP results for both of these. I don't have the "high-risk" allele for either gene.
     
  8. nandixon

    nandixon Senior Member

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    My results are consistent with this study (risk allele for 23andMe users is in brackets):
    rs2247215 [G] AG
    rs356653 [A] AA
     
  9. alex3619

    alex3619 Senior Member

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    This point about random chance is a huge issue. Statistically each finding only has a small chance of being wrong, but with so many genes and so many findings how many are just artifacts of the investigative process? There does indeed need to be extensive follow-up work to find out if such findings are correct.

    If we can get just a few validated findings after weeding out the chance associations however, it will be a step forward.
     
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  10. alex3619

    alex3619 Senior Member

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    I rate the Empiric criteria as the second worst in the world after Oxford. Research based on it, like this study, should be considered suspect until they can prove their claims. So far they have not had a good track record. If the CDC touches it, it is probably wrong. However to be fair almost nobody had a good track record in ME until post 2000 or even post 2007. On the other hand, this is the CDC, the agency that has stuffed up so many times its a four letter word in our community ... oops, I miswrote (but not by accident) ;), it should be a four letter acronym. While most others got wise in the last six years, it looks very much like the CDC hasn't woken up to the modern science. That has to be the influence of either politics or dogma from where I sit, its not science.

    For those who have not read the paper, they used the Wichita surveillance study cohort.
     
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  11. Valentijn

    Valentijn Activity Level: 3

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    For rs2247215 [G], out of 12 ME/CFS patients 7 (58%) have AA, 4 (33%) have AG, and 1 (8%) has GG. Out of 15 controls, 4 (27%) have AA, 8 (53%) have AG, and 3 (20%) have GG. With a minor allele prevalence rate of 23.2% in the general population, 60% should be AA, 34.5% should be AG, and 5.5% should be GG. So the results look completely normal for ME/CFS patients from this forum, and control rates are pretty normal too, especially for a European population.

    For rs356653 [A], out of 12 ME/CFS patients 6 (50%) have GG, 4 have AG (33%), and 2 (17%) have AA. Out of 15 controls, 5 (33%) have GG, 8 (53%) have AG, and 2 (13%) have AA. With a minor allele prevalence rate of 39.9% in the general population, 36.1% should be GG, 48% should be AG, and 15.9% should be AA. So again, we really aren't showing more A alleles than would be expected.

    However is interesting that they found less GRIK2 expression and elevated NPAS2 expression. I'll take a look and see if the other tested SNPs on those genes show anything interesting.
     
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  12. Gijs

    Gijs Senior Member

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    These genes have not much to do with our symptoms only memory loss but we do not have mental retardation. This study is useless. But what else do we expect from the CDC.
     
  13. alex3619

    alex3619 Senior Member

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    NPAS2 is involved in regulating the circadian clock. Many of us have altered sleep cycles. I wouldn't rule it entirely out just yet.

    GRIK2 might explain brain fog. Its complete knockout is what causes retardation, but what if its only working 90% ?

    I still don't trust CDC data though. They will have to work hard to convince me. I think we should be highly sceptical, but I also think we should demand better science than what the CDC usually does to see if there is something to this.
     
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  14. GaryK

    GaryK

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    Alex I agree with your line of thinking its a funtional % of these Genes not working properly that could very well be the issue and not look at it as an It works or it doesnt work Senario.

    I think we see this in "The Mitochondral System.
     
  15. nandixon

    nandixon Senior Member

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    Yes, this is mainly why I brought this 2011 study back up again (now that more people have done 23andMe testing).

    I have serious circadian rhythm problems (not uncommon in ME/ CFS), and I already knew I had multiple bad homozygous results for many of the SNPs in the CLOCK gene.

    I didn't realize that NPAS2 had a CLOCK-like role as well. So it gives another gene to look at in addition to CLOCK for some our sleep cycle difficulties.
     
  16. A.B.

    A.B. Senior Member

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    Mercury exposure also results in glutamate mediated excitotoxicity.
     
  17. alex3619

    alex3619 Senior Member

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    I don't have links handy, but a few years ago I realized we have another issue. High oxidative stress in the hypothalamus stuffs up our clock, and disrupts sleep. However this stuffs up liver regulation of fat metabolism, which then leads to lower energy and fatty liver, and predisposes to diabetes.

    So many of these symptoms are interconnected. Its currently not a nice simple problem, like A causes B, where you can pick up the spaghetti strand of causation and cut it. Its more like a huge pot of tangled spaghetti, and we cut and cut and cut in the hopes of finding the one cut that makes it go away. Some pick up one strand of spaghetti and boldly announce this is the cause, others choose a different strand, and still others say the strands look like string, its really caused by string.
     
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  18. Valentijn

    Valentijn Activity Level: 3

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    I've looked at GRIK2 23andMe results for the 11 ME/CFS patients I have full data for, compared to 11 controls. If any control or patient has a genotype present in 10% or less of the population, it's included in the chart. 0-1% = purple, 1-2.5% = red, 2.5-5% = orange, 5-10% = yellow, 10%+ = white.

    GRIK2.gif

    Basically it's a fairly big and funky gene, where pretty much everyone has at least some uncommon SNPs. But as a group, we do have more rare genotypes than the controls. We have 6 SNPs on the gene present in less than 1% of the population, versus 2 for controls. And 16 SNPs present in 1-2.5% of the population compared to 6 in controls. Weighted totals are also shown it the "TOTAL" row at the very end.

    It's also likely that ME/CFS patients have glutamate problems in general - the rare gene analysis program brings up very rare homozygous glutamate SNPs for pretty much every patient I've looked at thus far, albeit often on different genes.
     
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  19. Marco

    Marco Old blackguard

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    Might I suggest that rare mutations in genes such as GRIK2 and COMT are not directly related to ME/CFS (i.e. direct causation - although they may contribute to a range of 'stressors') but may help determine the range of symptoms an individual develops after onset?
     
  20. Valentijn

    Valentijn Activity Level: 3

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    NPAS2 results, with the same formatting as described above for GRIK2:

    NPAS2.gif

    We're looking pretty similar to the controls for this gene.
     

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