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Interesting CBS Variations

Discussion in 'Genetic Testing and SNPs' started by Valentijn, Jul 30, 2013.

  1. Valentijn

    Valentijn Activity Level: 3

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    These are the CBS SNPs from the 23andMe test, which have research showing if a genotype or allele is risky. The primary risk factor associated with CBS mutations is elevated homocysteine due to downregulation of the CBS gene. Two of the SNP variations are considered "protective" in the research, meaning they are upregulated and help in disposing of homocysteine a bit faster than normal.

    Thus the the CBS C699T SNP which Yasko reports as AA being the risky version, is reported here with GG being the riskier version. No studies showed any increased risk due to the A allele, and two studies showed less risk for two separate disease. Similarly, CBS A360A and CBS N212N have no risk associated with any variation in any available research, hence are not included in the list.

    Missense mutations are underlined, bolded, and orange. Even the very rare and serious CBS mutations are usually treatable with vitamin B6, in the case studies discussing them (they rarely have bigger studies because the mutations are too rare). Hence it's likely that B6 is helpful in the milder mutations as well. It's possible that even one mutation in the missense mutations is relevant to CBS gene function, albeit to a milder extent.

    rsID.........NAME....RISK...ETC
    rs121964968..L539S...GG....i5003392
    rs6586282....G134A...CC...T is protective
    rs28934891...D444N...TT
    rs28934892...P422L...A
    rs121964967..K384E...CC...i5003393
    rs121964972..T353M...A....i5003389
    rs4920037....C530T...A
    rs5742905....I278T...G
    rs121964969..R266K...T....i5900470
    rs234706.....C699T...GG...A is protective
    rs121964970..V168M...T....i5003391
    rs121964963..P145L...A....i5003397
    rs121964966..E144K...T....i5003394
    rs121964964..A114V...A....i5003396
    rs234709.....G477A...T
    rs234715.....C224A...T
    juniemarie likes this.
  2. Valentijn

    Valentijn Activity Level: 3

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    So what is CBS and why is it relevant?

    "CBS" stands for cystathione beta synthase, an enzyme created by the CBS gene with the same name. It converts homocysteine into cystathionine, using B6 (pyridoxal-phosphate) as a cofactor. Cystathionine can then be converted into cysteine, which can be quite helpful in general and for ME patients in particular, as cysteine then goes on to combine with other amino acids to create glutathione.
    Little Bluestem, ukxmrv and SOC like this.
  3. Bluebell

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

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    Valentijn, if it's been shown that CBS mutations are treatable with vitamin B6, is there any consensus in those reports about how much B6? Are they talking about the amount in a daily multi or much more?

    For all of these genes that you are looking at (in your series here and in your 23andMe data analysis program), will you be identifying the references you have gotten your information from/based your analyses on, so people who are interested in the details can seek those sources out for in-depth reading?

    I've just looked up "missense mutation" on Wikipedia, so now I have something of an idea of what it is, but what is the "i" number in your "etc." column indicating? I'm not familiar with those.

    Lots of people here may already know about this stuff, but there will be some folks (it's hard to believe, but true!) who know even less than I do about genetics and biochemistry, and it would be helpful, I think, to include a little explanation of your basic terms, categories, and columns in each report in your "series".

    When you say that the one SNP interacts with C677T "AA" homozygous, how does it interact?
  4. Valentijn

    Valentijn Activity Level: 3

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    Much more would be a bad idea, since B6 is toxic in high doses and can cause neuropathy.
    Yes, and the analysis program is already set up to generate a list of sources along with the results.
    Those are the numbers given by 23andMe when they want to hide the rsID. So if you're looking for the rsID for those SNPs, you won't find it in your results, but you can find the "i" number.

    Yeah, either on the report or on the site somewhere, with a URL for the explanation listed on the report.
    Now that I've read the paper again, I think the "interaction" effect is just imprecise wording in the study - they seem to be referring to both genes "interacting" with autism risk and/or lack of vitamin supplementation, rather than the genes interacting with each other. At any rate the values given where they talk about interaction are the same as in Table III where they're looking at each SNP separately. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116691/). I'll remove that note, since the SNP is significant on its own.

    Though as an interesting side note, C677T makes even some of the more severe MTHFR mutations about twice as bad.
  5. Bluebell

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

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    Well, obviously a toxic dose wouldn't be a therapeutic, recommended dose. (not for long, anyway)

    If I had these mutations, I'd ask you how much B6 the studies/reports recommended/tested exactly (like in mgs!) but I don't, so I won't. :)

    Where do you enter in an "i" number in 23andMe? In the rs number box?

    Oh, groan, wait a min, is this the thing you've mentioned before where you have to look at the actual string of little letters and magnify it or something on the government's website? Bleurgh, I don't see myself doing that much :ill:
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  6. Valentijn

    Valentijn Activity Level: 3

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    :rolleyes:
    Good, because I haven't looked :p Basically some mutations are considered "pathological", and those are the ones where a specialist does a case study on them. Those ones tend to be quite severe, with little or no enzyme activity, whereas the relevant non-pathological mutations tend to vary between being suboptimal and technically deficient. So the advice on dosage probably varies depending on which SNP has gone belly-up. For the more common ones, supplementing a normal RDA dosage is probably plenty.
    Yes! And I'm putting the SNPs in the same order that they're in in 23andMe, so it should be easy to scroll down through the results if you don't want to "search" for each SNP.
    That's how I find the rsID and associated research when 23andMe gives an "i" number instead of the rsID. You can just use the "i" number :D
  7. Bluebell

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

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    That's handy!
  8. bel canto

    bel canto Senior Member

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    Thanks for all the information, Valentijn.

    Why would 23and me want to "hide" the rs numbers?
  9. Valentijn

    Valentijn Activity Level: 3

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    Either to protect us from knowing we're sick (they do this for diseases on their site, and you have to unlock your status to see if you have it), or for financial reasons. Financial reasons might include letting a specific company study the prevalence and phenotypes of the users (for a fee, and only if the users consent), or plans to offer a service regarding these SNPs in the future.

    No idea, really.
  10. juniemarie

    juniemarie Senior Member

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    I have added B6 in the form of P5P and it has helped me quite a bit.........But I have added other stuff too so I cant say for sure it was the P5P Its sublingual I am adding the b's one at a time I can say for sure that its not causing crashes or problems for me, at least so far. I have been on it about 8 weeks.
    Valentijn likes this.
  11. I am sorry, still new to this, but am confused about CBS C699T. My genetic genie says I am AA (++) and describes addressing taurine, ammonia and sulfur groups. but above you say that

    "rs234706.....C699T...GG...A is protective"

    Can you see why I am confused? thanks
  12. Valentijn

    Valentijn Activity Level: 3

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    Yes, and I'm afraid you can blame your confusion on bioengineered mutant yeasts and Down's Syndrome. :D

    Basically in Down's Syndrome there are three copies of the chromosome that CBS, instead of two, which can result in drastic upregulation of the CBS gene, thus very low homocysteine and quite possibly higher sulfur, ammonia, etc. Thus some people believe (without evidence) that the CBS gene is capable of replicating this feat with only two copies of CBS.

    There is also a study where someone took the CBS gene, chopped a bunch of it off, put it into a mutant yeast, and gave it a poke to see what happens. Basically the functionality was dramatically affected, to the tune of 10x the usual activity.

    So someone seems to have reasoned that because one version of C699T is faster than the other versions, and Down's Syndrome is a potentially bad upregulation, and hacked mutant yeast is an upregulation, the C699T upregulation must somehow cause the same effect as hacking up the entire CBS gene in a mutant yeast and the elevated sulfur of Down's Syndrome. I can't explain it any further than that - it's all very illogical.

    But if you read the research involving C699T, every study shows bad effects for G. Two that I made a note of include A resulting in less cleft palate (birth defects often associated with insufficient folate, etc) and less adenomas. It also results in lower homocysteine, which is almost always a very good thing.
    roxie60 likes this.
  13. So basically - should I get my ammonia, taurine and sulfite levels checked? Its £180 through Genova!!!!
  14. Valentijn

    Valentijn Activity Level: 3

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    Your C699T doesn't give any reason to think that you have an ammonia or sulfur problem. If you really need to know, then I suppose testing is the way to go, but unless you have specific reason to think you have those problems, it seems like a rather random thing to test for.
  15. ;) thanks - just trying to decipher the genetic genie advise
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  16. roxie60

    roxie60 Senior Member

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    Valentijn So you are saying C699T GG is actually the bad one (+/+ even though genetic genie gens -/-) and the 'A' alleles are the no / low dysfunction? That makes more sence to me now, I am GG but I had recorded it as -/-. All my homosysteine tests come back at the low end of the range so that would fit with my labs that the C699T GG is the risk allele (although in this case bad in good related to homocycteine ;) ).

    Edit: I reread, so it seems I have it backwards. GG mutation should mean higher homocysteine? I reread first thread. But lower thread posts seem to suggest lower homocystiene if have the risk version GG. If CBS C699T is a down regulator and on has 'GG' then homocyteine should be lower, correct? Is this another one of those if it is bad gene it is actually good ? I seem to have problems with P5P (B6), makes me brain foggy, more fatigue, and no I haven't figured out why yet.

    Edit edit: reread a thrid time and conculde GG should mean higher homocystiene. I have 'GG' but my homocystiene when tested has been on the low end of range. So still confused. Something else must be mucking up the works, now concerned if get everything working that might end up with high homocystiene. Catch 22. Is my conclussion about GG and higher homocystiene correct?
  17. roxie60

    roxie60 Senior Member

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    Is there a study I can read regarding this statement:

    interesting side note, C677T makes even some of the more severe MTHFR mutations about twice as bad.

    Also do you really mean C699T, and not C677T?
  18. roxie60

    roxie60 Senior Member

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    when tested my ammonia, taurine, glutathione are low but sulfate is at very high end of range.
  19. Bluebell

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

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    I think she was talking about MTHFR C677T.

    The wording was confusing, I will agree with you (as if C677T were not also an MTHFR mutation).

    I think she meant, "...makes even some of the other, more severe MTHFR mutations about twice as bad."

    The only one I know of is this one -- a hetero MTHFR C677T does make a hetero MTHFR A1298C worse than when a hetero MTHFR A1298C appears on its own.

    But maybe she was talking about CBS C699T. (Early dementia - been putting too much hacked mutant yeast in her cinna-bonita bread.)

    ----
    Valentijn, if you ARE talking about MTHFR C677T here, can you say what the "more severe MTHFR mutations" are -- what are their rs numbers? Are these ones that 23andMe reports on?
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  20. Valentijn

    Valentijn Activity Level: 3

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    Indeed, there are some that are worse than MTHFR C677T. MTHFR W339G (rs267606886) CC reduces gene functioning to 21% of normal, and MTHFR N324S (rs267606887) CC reduces gene functioning to 36% of normal. There's also another MTHFR SNP which takes it down to 10%, but isn't part of the 23andMe results.

    When C677T is added to the mix, functionality of those reduces by half again. So W339G is then down to about 10%, and N324S to 18%.

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