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HPA and Serotonin Transporter gene polymorphism and CFS

Discussion in 'Latest ME/CFS Research' started by roxie60, Jul 5, 2013.

  1. roxie60

    roxie60 Senior Member

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    Found this article/research. Just cant find the gene or SNP they are refering to in 23andME. Anyone else after readin this have an idea which gene SNP (s) they are refering to, I would like to look up in raw data. I have has neurotransmitter issues for years so I am curious how my genes line up with this research.

    http://www.cfids-cab.org/cfs-inform/Genes/narita.etal03.pdf
  2. roxie60

    roxie60 Senior Member

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    Not sure where to put this article but it found high correlation with certain SNPs and CFS.

    http://www.cfids-cab.org/cfs-inform/Genes/goertzel.etal06.pdf

    Maybe someone can help interpret Table 3. I have read the text a few times and I dont think the Alelle frequency is refering the actual alelles. It seems they are reporting some type of model but they sure confuse th topic by listing Alelle frequency columns, I was inclined to try and figure out which column fit with which alelle (homo, hetero and risk allele) but I think I may not be correct to do so. Makes me wonder how to identify which is the risk alelle and its frequency of occurence in CFS subjects.:confused::confused:

    Rs933271 CC seems to be rare for European population which is what I have.
  3. roxie60

    roxie60 Senior Member

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    tired looking for some answers.
  4. Valentijn

    Valentijn Activity Level: 3

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    For a lot of SNPs there aren't RS numbers (or weren't when this study was run), so things are described based on their location. In this case the gene is using an old name, which makes things harder. If you go to www.ncbi.nlm.nih.gov/gene/ and search for "5-HTTLPR", the first result (SLC6A4) has that listed as an alternative name.

    Then it says this abnormality is in the "5' upstream region", which means it's at one end of the gene. If you're on the gene page, you can go to the "map" and scroll til the left end of the gene is in the center of the screen, then zoom in a bit. If you click on the rsIDs which appear, you can see (right above their map on the new page) that their "Function" is given as "UTR-5". So you're in the right neighborhood, and the results they're talking about are somewhere in that part of the gene where it's showing the thicker band.

    Unfortunately, it's hard to make a direct comparison between that study and your 23andMe results. That study is looking at an entire "sentence", whereas 23andMe is just sampling a few letters from that sentence. But they're looking at length of sequences, which might suggest an insertion or deletion SNP. So it might be possible to check all of the UTR-5 SNPs to see if any are deletion or insertion SNPs, or check your results from that gene in your 23andMe results to see if there's any DD, II, DI, or maybe even -- results.

    The only 23andMe SNPs in the UTR-5 are rs28914824 and rs25533. Though a few more are shortly after it and listed as being associated with the gene when viewing them: rs28914823, rs2321495, rs25532, rs25531, rs28914822. You can also search for the priming sequences using the gene view to get the actual location on the chromosome.

    The first flanking sequence ends at 28,564,494 and the 2nd flanking sequence starts at 28,564,007. If you zoom out until you can see that entire range, there's a bunch of SNPs in there with data about them. You can also look for those ranges (on chromosome 17) on your 23andMe results to see which SNPs are reported that are in that range: rs25532 and rs25531.

    For rs25532 I have the normal "GG" and for rs25531 I have "--". Does the "--" mean I have something other than an expected result, possibly as the result of an earlier insertion or deletion? No idea! :confused: The study doesn't give the alternative allele sequence, only stating that it's longer. And even if it did give the alternative, I still have the "--" which isn't going to help me anyhow.
    roxie60 and Shell like this.
  5. Shell

    Shell Senior Member

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    Thank you for the explanation Valentijn I'll come back when I don't feel like a zombie who just licked a toad.
  6. Valentijn

    Valentijn Activity Level: 3

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    Well there's your problem - zombies are supposed to EAT the toad :D
    Shell likes this.
  7. Shell

    Shell Senior Member

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    Ah to be a zombie!
  8. Shell

    Shell Senior Member

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    Ok, I may be completely misunderstanding this study but - is it suggesting there's a genetic predisposition to HPA axis dysfunction in people with a dx of CFS (presumably depending on what dx crit is used)?
    HPA axis dysfunction seems to be part of hyperadrenergic POTS and HyperPOTs is found in lots of people with a dx of FMS.
    Would this suggest that ME-CFS-FMS could be the same disease on a spectrum and is actually a form of dysautonomia?
    But then according to Simpson in his book on "Ramsay's Disease" Ramsay excluded dysauto patients from a dx of ME.

    Having said that I would assume that although hyperPOTS is dysauto that HPA stuff is endocrine...AAAARGH. I don't understand this...
    Another toad methinks.
  9. Valentijn

    Valentijn Activity Level: 3

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    My interpretation is that having these extra long bits on the 5-HTTLPR gene means that more serotonin is taken up, resulting in lower serotonin levels, which results in increased susceptibility to HPA dysfunction. And the HPA dysfunction results in increased susceptibility to CFS.

    They're using CDC definition, so it's hard to tell exactly what they're studying, especially since they describe "fatigue, sleep, appetite(?!?), pain, and inflammation" problems, but not PEM or OI. So I think the stupid definition is making them think CFS is a lot more one-dimensional than it is, hence that an SSRI will cure/significantly improve 25% of patients.

    They also fail to state what the allele lengths were for the cured patients, so there's probably no correlation between what they found in this study and the effectiveness of the "cure" for some CFS patients.
    I wouldn't read too much into their theorizing about serotonin and such. Due to the crappy definition used, this research is pretty useless for everyone, except perhaps suggesting that looking into 5-HTTLPR allele length in properly defined cohorts might be interesting.
    :thumbsup:
  10. Bluebell

    Bluebell More % Neanderthal than Adreno but less hairy :-D

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    V, that gave me a brain infarction, but right now my head is full to the brim after too many hours online!

    I just wanted to say that this sort of explanation of how to decipher various 'unfamiliar' (meaning, in my case at least, not providing a simple rs number that can just be punched into 23andme!) conventions for naming the genes/alleles/SNPs/whatnot, as they appear in medical/research journal articles, etc., fulfils an educational need for folks who don't know much about this subject matter, and maybe it would be an idea to have a section/page on your analysis program's website containing these step-by-step directions....?
    Valentijn likes this.
  11. Valentijn

    Valentijn Activity Level: 3

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    Yeah, it's been largely a matter of trial and error - mostly error :p But it's pretty cool figuring out some of the ways the government's genetic database can be used, like zooming in and out to find specific locations on a chromosome (and seeing the SNPs with RS numbers there), or doing searches for primer sequences, since a lot of studies talk about those when they don't list locations or RS numbers.

    It turns out that a ton of the "i" numbers from 23andMe are actually pathological and/or missense SNPs which have existing RS numbers. So a lot of useful information is being hidden that way, but now I know how to find it with the location information :nerd:
    Shell likes this.
  12. Bluebell

    Bluebell More % Neanderthal than Adreno but less hairy :-D

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    I totally concur with everything you say regarding the fascinating "i" numbers, though I have no idea what you are talking about. ;)

    Now I have the giggles, I think I'm overtired. :sleep:

    :sluggish: Why does that guy indicate sluggishness - to me he looks like he's crawling for his life after seeing a ghost. He is more animated than I am!

    :thumbdown: I think this little guy looks a bit weird - who holds his hand right up near his temple to do a thumbs-down sign?
    I have been assuming that he was scratching his head in confusion. (My vision is blurry.) Good thing I didn't use him as an emoticon, because that would have been unintentionally insulting!

    ---
    Sorry to have kind of crashed your thread, Roxie60 - I hope you have found the answers you were looking for in that paper.
    Shell likes this.
  13. roxie60

    roxie60 Senior Member

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    Thx, not sure I have but I am curious how one translate i numbers into their 'secret' rs numbers. why o they have to make is so hard???
  14. Valentijn

    Valentijn Activity Level: 3

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    You have to go to the gene and zoom in and out and scroll left and right with the little graph thing until you find the "location", which 23andMe does list with the "i" numbers.
    roxie60 likes this.

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