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Nitric oxide and its possible implication in ME/CFS (Part 1 of 2)
Andrew Gladman explores the current and historic hypotheses relating to nitric oxide problems in ME/CFS. Part 1 of a 2-part series puts nitric oxide under the microscope and explores what it is, what it does and why it is so frequently discussed in the world of ME/CFS. Part 1 focuses...
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  1. SickOfSickness

    SickOfSickness Senior Member

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    This may already be on the forum, but I found you can browse raw data on 23andme and search for these genes. Then you look for deletions, insertions, or a combination. They would be DD, II, or DI.

    I'm a beginner at SNPs, so I hope I am doing it right. I'd be glad to learn more, so if anyone knows, please post.

    I searched on each of these below. I think there are more to check for other collagen disorders?
    "Mutations in the ADAMTS2, COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, PLOD1, and TNXB genes cause Ehlers-Danlos syndrome."
     
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  2. PennyIA

    PennyIA Senior Member

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    I'm looking at my 23andMe data as well, though I have so far only looked at COL3A1. I don't have any identified as DD, II, or DI...

    but I did find that SNP rs1801184 has been linked to vascular EDS testing as a possible indicator

    What I don't know is if I'm reading this correctly?


    Gene: COL3A1
    Position: 189864582
    SNP: rs1801184
    Possible values: C or T
    My values: CC

    - per dbSNP, TT is normal; CC is not rare; but when searched in PubMed/Google Scholar T>C is linked with Vascular EDS.


    ----- I've looked at a high level at EDS and threw it out because a lot of the visible physical symptoms don't seem to apply. And I certainly don't have hypermobility; although I am a bit more flexible than most people, no where near what is described in a lot of the EDS literature.

    And then I just got back from a colonoscopy where they found several pockets of diverticulosis. Nothing to worry about, they said, that's really common if you have constipation. Only, I NEVER, EVER, EVER have constipation. NEVER. I spend 80% of my days on the pot from chronic diahrrea... so I looked at one of the other causes which includes vascular EDS. AND when I look at vascular EDS, it lists several side effects that my mother went through... she was diagnosed with Fibromyalgia which I believe was either misdiagnosed ME/CFS or comorbid; but suffered several anuerysms (weak arteries), thin skin that bruised and tore easily, early onset varicose veins that re-occurred multiple times after surgery, pelvic floor prolapse (which might be linked but isn't considered diagnostic) and actually died of inner cranial bleeding (weak blood vessels).

    While I don't think diverculosis is all that telling, I suffer frequently with torn tendons and I see the chiropractor ALL THE TIME because my back is constantly sublaxing even after regular treatment. To the point where they keep referring me to a new chiropractor because it's not normal to not stabilize after nth year of considerable treatment to reach a point where the adjustment can last longer than a day or two. As well as spontaneous dislocation of ribs multiple times - weak collagen seems like it might be a link. If you add my mother's history, it feels like more of a link.

    So, now... I've seen links to the SNP to Vascular EDS. If I have the 'abnormal' gene I think I want to take it to a doctor. But, I can't be sure I'm following things right from looking at 23andMe (I've misunderstood stuff from them often)...

    What do you think my next steps might be???
     
  3. Valentijn

    Valentijn Activity Level: 3

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    @PennyIA - How is it linked to EDS? I just see one study where it was looked at but no association was found, and another study which is just talking about a method for detecting the variants, not the impacts of them.

    Which study are you looking at?
     
  4. PennyIA

    PennyIA Senior Member

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    That's what I'm hoping to verify. (I'm not sure I'm reading the technical jargon correctly)

    A novel mutation screening system for Ehlers-Danlos Syndrome, vascular type by high-resolution melting curve analysis in combination with small amplicon genotyping using genomic DNA.

    http://www.ncbi.nlm.nih.gov/pubmed/21219851

    Abstract

    Ehlers-Danlos syndrome, vascular type (vEDS) (MIM #130050) is an autosomal dominant disorder caused by type III procollagen gene (COL3A1) mutations. Most COL3A1 mutations are detected by using total RNA from patient-derived fibroblasts, which requires an invasive skin biopsy. High-resolution melting curve analysis (hrMCA) has recently been developed as a post-PCR mutation scanning method which enables simple, rapid, cost-effective, and highly sensitive mutation screening of large genes. We established a hrMCA method to screen for COL3A1 mutations using genomic DNA. PCR primers pairs for COL3A1 (52 amplicons) were designed to cover all coding regions of the 52 exons, including the splicing sites. We used 15 DNA samples (8 validation samples and 7 samples of clinically suspected vEDS patients) in this study. The eight known COL3A1 mutations in validation samples were all successfully detected by the hrMCA. In addition, we identified five novel COL3A1 mutations, including one deletion (c.2187delA) and one nonsense mutation (c.2992C>T) that could not be determined by the conventional total RNA method.

    Furthermore, we established a small amplicon genotyping (SAG) method for detecting three high frequency coding-region SNPs (rs1800255:G>A,
    rs1801184:T>C,
    and rs2271683:A>G) in COL3A1 to differentiate mutations before sequencing.


    T
    he use of hrMCA in combination with SAG from genomic DNA enables rapid detection of COL3A1 mutations with high efficiency and specificity. A better understanding of the genotype-phenotype correlation inCOL3A1 using this method will lead to improve in diagnosis and treatment.


    From reading the full article what I was able to discern was that there was concern about whether or not it was accurate enough to do standard DNA testing, which may mean that 23andMe info might not be useful... but before I even get there? I can't quite decipher if this is one of the key coding errors to look for.


    I guess what I was seeing, wasn't making sense as it was fairly common defect according to the 'populations' and yet, I can't obviously connect it to something that says - this specific defect is one of the defects that indicate EDS.
     
    Last edited: Dec 11, 2014
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  5. PennyIA

    PennyIA Senior Member

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    Using info from @SickOfSickness, I looked at the other genes he listed (I'd only been looking at COL1A1) and only looking at DD, DI, or II values as opposed to trying to figure out if the values I have are tied to EDS.

    I am finding the following: over 40 II and DD items on COL1A1, about a handful on COL1A2;

    So, as I'm looking - I see a handful of studies ruling them out for specific types of EDS. What I know is that the family history and my own history alone would be laughed out of the office if I ask to be tested for EDS, because it's too indistinct, and inconclusive.

    But, I figure if I have the 23andme data and can find the right piece of data that is in indication to look deeper, we might be able to find some options... but I'm still just such a beginner when looking at this data.
     
  6. PennyIA

    PennyIA Senior Member

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    I think I'm just expecting too much too soon from current Genetics... I'm seeing a lot of information that defects in COL1A1 and COL1A2 cannot be linked to classic EDS, and nothing about them being linked to other EDS forms just due to deletions/insertions/etc... so I'd have to look at the individual values to identify substitutions... and every time I turn around I find that there's a different way to reference it, so if I'm looking at 100's of SNPs, I have to look in dbSNP and it'll show several names for that SNP that may or may not show in the EDS genetic database; but once I do find a match there, I can't tell if it's a control entry (non-EDS) or indicitive of an EDS patient.
     
  7. Sea

    Sea Senior Member

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    It is early days yet for discovering the genetic bases of EDS. One of the most helpful sites for discovering connections is
    http://ghr.nlm.nih.gov/condition/ehlers-danlos-syndrome/show/OMIM

    Keep clicking on links until you find "allelic variants"

    One of the frustrations though is that 23andme doesn't test for lots of the snps that you will find listed
     
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  8. FightingCFS

    FightingCFS

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    I was quite impressed with the no of EDS related SNPs in 23andMe's current chip. There may be more or less in the v3 chip-- not sure of that just yet. It'll be great if someone with the old raw data chip can confirm. For now though, these are the EDS SNPs I was able to run with my v4 raw data. I think you'd need a free acc to see this report but it's a great starting point for those of us who are just starting to learn: https://livewello.com/snps/library?action=preview&index=204070&for=demo
     
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  9. PennyIA

    PennyIA Senior Member

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    Hmmm... so I pulled down a few variance reports that were all 'genes being studied' with links to EDS, as opposed to proven.

    Then I went back and found the variance report you had linked, and it states that it's screening for:

    The part that makes me struggle is that it's at least telling me I'm heterozygous for one defect on ADAMTS2 (EDS) and heterozygous & homozygous for two defects that cause another connective tissue disorder - Loeys-Dietz syndrome type II.

    But then it gives information at the gene level and 'several snps' in this gene cause this condition... but when I try to pull up any reports that include the specific snp's identified in the report, I'm not finding studies that help me go 'yes - that's the info'... and none of these seem all that rare in any of the population 'clusters' on dbsnp.

    BUT, at least it gets me to the subset of genes taht I would consider digging deeper into... which is better than where I was at yesterday!

    https://livewello.com/snps/share?index=893296&for=penny.heeren.33
     
  10. Sea

    Sea Senior Member

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    The livewello reports are put there by anyone, there is no guarantee they are accurate. I've looked at their list for EDS before and they are very incomplete. Whoever has done them has just included all snps on the particular genes rather than ones known to be relevant. Also, they've only included the ones listed by rs numbers whereas many of the important ones are in 23andme under i numbers instead. It takes a bit of work to find out the corresponding rs numbers for those i numbers.

    Edit to add
    Ok, I've looked at the Livewello site again and I now realise that the reports are done by Livewello not by the individuals sharing them. I still question their accuracy and they're still missing the i numbers
     
    Last edited: Dec 12, 2014
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  11. PennyIA

    PennyIA Senior Member

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    I think only the standard variance reports are done by Livewello. They don't have a standard variance report on EDS, and yes, you are right - those were done by others and anyone can add them - and in fact, I saw the names of the people who had submitted each one.

    That's why I was trying to follow through for each snp that appears in the report as a 'variant' to try to tie it to research papers. No joy there, either.

    But, the key here though is that at least I'm only looking at a few dozen discrepencies instead of looking at every snp on every gene to try to figure out first if my result was normal or unexpected. And I think that's still possible prone to inaccuracies. If I remember the info I read early on indicated that you could run Yasko's panel to see things - and I know that folks have indicated that there's at least one error in her interpretations; which could be replicated in that variance report. (I didn't go look at mine).

    I spent hours last night after work looking at these variance reports and trying to dig up more details and not getting very far... so I think now that I still just have a suspicion and no clear evidence; just defects in the same genes with no way of knowing if they are truly applicable or not...

    I'm going to take some of the better descriptions of symptoms related to the couple of EDS and Loeys-Dietz syndrome's ... and highlight the ones that affected my mom that I know of... and another copy and highlight the ones that I know I have and see if it's still 99% white or more than 50% highlighted. I'll use that to determine if I can convince the doctor to send me for further testing.
     
  12. Sea

    Sea Senior Member

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    Did you look at the OMIM link Penny? It would narrow your search.
     

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