Invest in ME Conference 12: First Class in Every Way
OverTheHills wraps up our series of articles on this year's 12th Invest in ME International Conference (IIMEC12) in London with some reflections on her experience as a patient attending the conference for the first time.
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Mitochondrial DNA variants correlate with symptoms in ME/CFS

Discussion in 'Latest ME/CFS Research' started by Marky90, Jan 20, 2016.

  1. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    Abstract
    Background
    Mitochondrial dysfunction has been hypothesized to occur in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a disease characterized by fatigue, cognitive difficulties, pain, malaise, and exercise intolerance. We investigated whether haplogroup, single nucleotide polymorphisms (SNPs), or heteroplasmy of mitochondrial DNA (mtDNA) were associated with health status and/or symptoms.

    Methods
    Illumina sequencing of PCR-amplified mtDNA was performed to analyze sequence and extent of heteroplasmy of mtDNAs of 193 cases and 196 age- and gender-matched controls from DNA samples collected by the Chronic Fatigue Initiative. Association testing was carried out to examine possible correlations of mitochondrial sequences with case/control status and symptom constellation and severity as reported by subjects on Short Form-36 and DePaul Symptom Questionnaires.

    Results
    No ME/CFS subject exhibited known disease-causing mtDNA mutations. Extent of heteroplasmy was low in all subjects. Although no association between mtDNA SNPs and ME/CFS vs. healthy status was observed, haplogroups J, U and H as well as eight SNPs in ME/CFS cases were significantly associated with individual symptoms, symptom clusters, or symptom severity.

    Conclusions
    Analysis of mitochondrial genomes in ME/CFS cases indicates that individuals of a certain haplogroup or carrying specific SNPs are more likely to exhibit certain neurological, inflammatory, and/or gastrointestinal symptoms. No increase in susceptibility to ME/CFS of individuals carrying particular mitochondrial genomes or SNPs was observed.

    Link: http://www.translational-medicine.com/content/14/1/19

    Is it right to deduct that this study does not support the hypophesis that ME/CFS could be a mitochondrial disease in a subset?
     
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  2. ukxmrv

    ukxmrv Senior Member

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    I'm taking it as meaning that it is only ruling out an association with mtDNA SNPs that they tested. It could still be an acquired mitochondrial disease. I don't know how thorough their mtDNA testing was or how understood this area is in general

    Hopefully someone else will understand it better than I do.

    They have however reported that different Halpogroups could be more implicated but these are really common European ones. We did a poll a while back on this forum of Halpogroups.

    p.s. I thought this is interesting

    "We did not observe a significant association of mitochondrial DNA genome variation with either susceptibility or resistance to ME/CFS. We did not detect any significant difference in level of heteroplasmy between cases and controls. Using a cohort of 193 ME/CFS cases and 196 controls, at 5 % FDR we observed eight mtDNA SNPs to be associated with 16 symptom categories and three haplogroups associated with six symptom categories, suggesting that the mitochondrial genome of an individual with ME/CFS can affect the type and severity of particular symptoms."
     
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  3. lansbergen

    lansbergen Senior Member

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    No higher susceptibility but assosiation with symptom exhibition.
     
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  4. Bob

    Bob

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    Posting these details so the thread will show up in a search...

    Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome
    Paul Billing-Ross, Arnaud Germain, Kaixiong Ye, Alon Keinan, Zhenglong Gu and Maureen R. Hanson.
    Journal of Translational Medicine 2016, 14:19
    doi:10.1186/s12967-016-0771-6
     
    Last edited: Jun 19, 2016
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  5. Simon

    Simon

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    Interesting stuff
    JTM | Full text | Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome

    I suspect I annoy some people with how often I bang on about problems of not correcting for multiple comparisons (p<0.05 only works for one comparison: the more comparisons you make, the more chance of a false positive with p<0.05). So I wanted to say how much I appreciate the authors taking the trouble to correct their data for false positives:
    Just to show what a difference it makes:
    Note how that exciting p value of 0.03 becomes an altogether irrelevant corrected p-value [aka q-value] of 0.6 (=nothing doing). That shows just how big a difference correction for multiple comparisons can make.

    In this case they were looking at 21 haplotypes ie 21 comparisons. I've seen many paper that make similar numbers of comparisons with NO correcction for many comparisons. I suspect this is a big issue in mecfs research.

    Yes, interesting given they did correct for multiple comparisons. Though worth noting that the results aren't hugely significant: the lowest one was p=0.023, and the other five p=0.039 or higher. (Table 3)
     
    Last edited: Jan 20, 2016
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  6. Bob

    Bob

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    Maureen Hanson has published a number of interesting and robust ME research studies. I'm very pleased that they are researching this particular area. It's an interesting study despite the results not being dramatic or particularly exciting. Unfortunately, I'm not sure if it gives us particularly useful leads.
     
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  7. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    Although this DNA stuff is above my head, i warmly welcome all research that narrows our approach down. I might have misunderstood something here, but is it not right that these findings make it at the very least - less likely - that ME in a subgroup is down to genetic pathology as the primary cause?

    Again, above my head this, so feel free to correct my assumptions violently.
     
  8. jimells

    jimells Senior Member

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    @Simon thank you for your analysis. I found it very informative. :thumbsup:
     
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  9. Valentijn

    Valentijn Senior Member

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    Not really. MTDNA (mitochondrial DNA) is a very very small part of the genome. But due to the symptoms that can be caused by mitochondrial diseases, it's often suspected of being involved in ME. So even if MTDNA was completely ruled out as causing ME, there's a great deal of other DNA which might still be the culprit.
     
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  10. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    I see, thanks! :)
     
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  11. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    Two follow up questions..

    How do one rule MTDNA completely out?

    And if MTDNA is ruled out, but other DNA was involved and hypothetically responsible, could ME still be labeled a mitochondrial disease?
     
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  12. Valentijn

    Valentijn Senior Member

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    Maybe by understanding the genetic code completely, and the impact which every SNP has (or doesn't have). And even in very well-conducted studies, some results have to be discarded because an allele is too infrequent or they don't get enough results in the whole group for a specific SNP.

    I think some broader types of analysis might also end up being useful. Instead of just making comparisons going SNP by SNP, it might be productive to go gene by gene. The same genetic disease is usually triggered by one of many different mutations on a single gene, with only minor differences in severity or symptoms of that disease depending on which mutation the individual patient has.
    I think this is an issue of "doctor/scientist lingo" versus "patient lingo". My understanding is that most doctors would only label something as a mitochondrial disease if it was due to an MTDNA mutation. Whereas patients are often referring to any dysfunction of the mitochondria as a mitochondrial disease, genetic or acquired.
     
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  13. shannah

    shannah Senior Member

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    Posting Ron Davis's recent remarks from a couple of weeks ago in The Stanford Daily in which is written:

    "The research team’s current model proposes that ME/CFS results from a type of mitochondrial dysfunction.

    “We’ve seen some evidence of mitochondrial dysfunction in the metabolites,” Davis said. “You don’t see that in mitochondrial diseases, so it’s probably not a genetic effect. No one has seen this kind of defect before, but it’s something we have to continue to explore. It would explain everything [including the brain function and fatigue].”

    http://www.stanforddaily.com/2016/01/05/tackling-chronic-fatigue-syndrome/
     
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  14. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    Thanks for a great article. That quote got my hopes up, and it sounds really really inriguing.

    Could autoimmunity cause that @Jonathan Edwards ?
    From what i have understood so far, autoimmunity can cause nearly anything..
     
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  15. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    If a mitochondrial defect is not genetic but it is persistent then autoimmunity is a reasonable possibility. Autoimmunity can cause whatever you like in theory. Maybe not quite everything in practice.
     
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  16. Kati

    Kati Patient in training

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    Mito dysfunctions can still be a downstream effect of the main problem and not the main cause. That's how I view it.

    And so we keep on searching.
     
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  17. GreyOwl

    GreyOwl Dx: strong belief system, avoidance, hypervigilant

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    I wonder about mtDNA deletions, which occur naturally with ageing (after about 80), but also following virus and toxin exposures. My daughter has deletions in MT-CO1, MT-ND5 and MT-ND6 which I don't share (so she has acquired those deletions at some point since her birth). Given that she was 8 when the sample was taken and has been sick since 5, that doesn't leave much time for her to have naturally acquired those deletions through ageing, especially since the number of deletions she has is twice mine anyway.

    I know there was an old study on this (http://www.ncf-net.org/pdf/ZhangMitochondrialDNAdeletionsInCFS.pdf) which I don't completely understand, but it's interesting that people are still looking at it.
     
  18. Bob

    Bob

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    Last edited: Jan 22, 2016
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  19. Bob

    Bob

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  20. Bob

    Bob

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