1. Patients launch $1.27 million crowdfunding campaign for ME/CFS gut microbiome study.
    Check out the website, Facebook and Twitter. Join in donate and spread the word!
Nitric oxide and its possible implication in ME/CFS (Part 2 of 2)
Andrew Gladman explores the current and historic hypotheses relating to nitric oxide problems in ME/CFS. This second article in 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....
Discuss the article on the Forums.

Interesting VDR Variations

Discussion in 'Genetic Testing and SNPs' started by Valentijn, Jul 29, 2013.

  1. Valentijn

    Valentijn Activity Level: 3

    Messages:
    6,510
    Likes:
    9,640
    Amersfoort, Netherlands
    These are all from the 23andMe test. Missense and stop-gain mutations are bolded, underlined, and orange. These all have research indicating that the risk allele is relevant. Downregulation of VDR seems to be associated with the risk in every case.

    rsID.........NAME....RISK...i#
    rs11574143...G3612A..T
    rs3847987....G461T...T
    rs121909800..R391C...AA...i5000776
    rs11574115...T362I...A?...rare
    rs731236.....Taq1....G
    rs267607169..V346M...TT...i5000773
    rs7975232....Apa1....A
    rs757343.....Tru91...C....TT is protective
    rs1544410....Bsm1....T
    rs121909802..E329K...T....i5000774
    rs121909799..I314S...CC...i5000777
    rs121909796..R271L...AA...i5000780
    rs121909795..Q149X...AA...i5000781
    rs2239182....A3419G..CC
    rs2239179....A1064G..T
    rs121909791..R70Q....TT...i5000785
    rs121909794..R47Q....TT...i5000782
    rs12717991...G166A...C
    rs886441.....C4004T..A
    rs3819545....T6046C..G
    rs3782905....C6584G..C
    rs2239186....T3341C..G
    rs121909797..G46D....AA...i5000779
    rs121909801..C88T....AA...i5000775
    rs2238136....G4817A..T
    rs2238135....G1633C..GG
    rs11168287...C8857T..GG
    rs4516035....A1012G..CC
    rs7139166....G1520C..CC
    rs11568820...CDX2....A
     
    Last edited: Jul 29, 2014
  2. SOC

    SOC Senior Member

    Messages:
    5,362
    Likes:
    6,423
    USA
    Valentijn -- What be this language ye be speakin'? ;)

    At the moment I don't understand a word of all this genetic-speak. :oops:

    I've been considering getting the 23andme testing, but am wondering if it is likely to change my treatment in any way. While it would be very interesting, I don't know if I'm in a place to get up to speed understanding what it all means. Are you finding it helpful?
     
    xchocoholic and Little Bluestem like this.
  3. Valentijn

    Valentijn Activity Level: 3

    Messages:
    6,510
    Likes:
    9,640
    Amersfoort, Netherlands
    I am finding it helpful. I was going to make a new post to elaborate on what VDR does and how to deal with problems, but since you asked I'll include it in this reply to you instead :D

    VDR is a gene which creates a receptor located inside of cells. The full name of the gene and the receptor which it makes is "Vitamin D Receptor" (hence "VDR"), or "Calcitriol Receptor".

    VDR doesn't make vitamin D, or transform it, or regulate it. VDR gets it's name because it's triggered by the final form of vitamin D called calcitriol. Calcitriol is the 1,25 vitamin D form that you might see mentioned elsewhere on the forum.

    When the Vitamin D Receptor is triggered by calcitriol, it does some very essential stuff. It regulates calcium levels in the body (which can include leeching calcium from bones when needed). In the process of regulating calcium absorption in the intestine, it also regulates phosphate absorption, since calcium and phosphate have to team up to be absorbed. The VDR also regulates immune response and has an impact upon developing cancer. And finally, there's been recent research indicating that VDR impacts upon neurotransmitter levels, especially dopamine, though the exact mechanism isn't clear yet.

    When the VDR is very dysfunctional, it can have a similar effect as vitamin D deficiency (rickets). This can result in low calcium, weak bones, low phosphate, and hair loss. But a VDR dysfunction can be harder to treat than a vitamin D deficiency, because a lack of vitamin D isn't the problem, and there's not a pill to take to get more VDR.

    In some extreme cases, VDR problems can cause Vitamin D-Resistant Rickets, where even massive doses of vitamin D have no impact - because there's no VDR for the vitamin D to interact with. But usually a high dose of vitamin D can help - possibly because high amounts of vitamin D helps to ensure that any existing VDR is going to encounter the vitamin D it needs to do its job. This might explain why some people are fine with a normal dose of vitamin D, while others only do better with much higher doses.

    So basically if there's a VDR problem, there can be symptoms of vitamin D deficiency even when vitamin D levels test as normal. In fact, having high levels of the calcitriol form of Vitamin D might indicate that it's not able to hook up with as much VDR as it should be hooking up with, and too much is left floating around.
     
  4. SOC

    SOC Senior Member

    Messages:
    5,362
    Likes:
    6,423
    USA
    @Valentijn~
    That is interesting. :) I definitely have some kind of Vitamin D issue. I thought I had had a 1,25 Vitamin D test, but it's not in my record. I'll have to look into that.
    A couple of years ago a Ca-Mg supplement I was taking was recalled because the manufacturer accidentally put in 10,000 times the listed amount of Vitamin D. My GP checked my Vit D (total) level and it was, unsurprisingly, very high. I felt really good when my Vit D was really high, though. Now I struggle to keep it above the minimum, even with large doses of Vit D. The having a hard time maintaining Vit D is not a VDR issue, but I wonder if the feeling a lot better when Vit D Total was high is.

    So, there's a lot more information available in 23andme testing -- beyond methylation factors -- that's useful to us? A VDR dysfunction could explain some of our problems, certainly.

    I think I will go for the 23andme testing once I'm earning money again in the fall -- as long as it's still around $100.
     
    Valentijn likes this.
  5. Valentijn

    Valentijn Activity Level: 3

    Messages:
    6,510
    Likes:
    9,640
    Amersfoort, Netherlands
    Definitely. It's mostly a matter of finding out which bits are useful. I'm hoping to pull out some of the useful bits for some of the genes that we talk about the most here.

    There's also sites like opensnp.org where you can make your data publicly available (after changing your name!), and be emailed a list of your very rare SNPs, which can also be useful in seeing where you have a relevant dysfunction.
     
    SOC likes this.
  6. nandixon

    nandixon Senior Member

    Messages:
    125
    Likes:
    117
    Hi Valentijn,

    Thanks very much for posting this. I've only gone through the first few SNPs in your original post but I think some of the risk alleles may not be correct:

    For rs3847987 I believe the risk allele is A; CC seems to confer protection.

    For rs757343, in 23andMe "plus" stand referencing, C is the major allele and T is the minor allele; I believe T is also the risk allele.

    I've only checked these through rs1544410 (Bsm1), so there may be others that might possibly be inconsistent. (I'm hetero for Taq1/Bsm1 and so didn't check to see what the actual risk alleles are there... Also, I don't have rs121909800 & rs267607169 in my 23andMe data and so didn't check those two either.)

    It may be a while before I check the remaining ones, so wanted to go ahead and let you know about the two that don't look right to me.

    Thanks again!
     
    Valentijn likes this.
  7. Valentijn

    Valentijn Activity Level: 3

    Messages:
    6,510
    Likes:
    9,640
    Amersfoort, Netherlands
    You're right ... I even had it that way in my notes, but just copied down CC :p
    Ah, yup ... I got "G" because the studies where looking at the reverse strand and I forgot to convert. But C is associated with increased prostate cancer risk in one study, and type I diabetes in another. I'll take another look to make sure it's the right way around.
    23andMe has those hidden using their "i" numbers. Hence the i number is given in the "Etc" column so you can find those.

    Thanks for the corrections - I think it's important that we be accurate! :D
     
    helen1 likes this.
  8. Sea

    Sea Senior Member

    Messages:
    741
    Likes:
    859
    NSW Australia
    Valentijn thanks for this. How do you find the snp rs numbers for what 23andme only report as i numbers? It's been frustrating me that I can't find info for them
     
  9. Valentijn

    Valentijn Activity Level: 3

    Messages:
    6,510
    Likes:
    9,640
    Amersfoort, Netherlands
    You have to go to the gene and navigate to the "position" on the chromosome. The easiest way is to go to a nearby rsID and see if there's an SNP nearby on the map.

    For example, i5000776 is located on VDR. 23andMe gives the location as 48,238,642. Right before it in the list of my 23andMe results is rs2229829 located at 48,238,607. If I lookup rs2229829 at http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=rs2229829 it shows a "Gene View" a little ways down, with a map of the chromosome.

    The green line going down the middle of the map is the rsID you're currently looking at. Because I'm at rs2229829, the map is zoomed on that location, and I know that i5000776 is nearby. Because 23andMe usually uses i numbers to hide the more interesting and pathogenic mutations, I look for a little purple box near the green line (since purple means "pathogenic allele").

    When hovering over it, the closest one shows the location as being 48238642. That's the one we want, so I can click on the rs# (variation ID) that pops up. If there's no big purple (or green, blue, yellow) boxes visible, you can scroll right and left by dragging the map, and zoom in and look for the little red boxes in the top row. If there's no boxes at the location, then it doesn't have an RS number.
     
    Critterina, nandixon and Sea like this.
  10. Valentijn

    Valentijn Activity Level: 3

    Messages:
    6,510
    Likes:
    9,640
    Amersfoort, Netherlands
    Okay, I reviewed the research!

    In source [1] below, G (C) is overtransmitted to affected children - this is a fancy way of saying that the kids with diabetes get more C than shows up in control populations (such as unaffected siblings). Hence it's showing an association between inheriting C from parents and ending up with Type I Diabetes.

    In source [3] below, the men with the combination of lowest vitamin D levels and a certain version of rs757343 have an increased risk of prostate cancer. Table III clarifies that that patient group has a small proportion of members with TT than the control group does. 69% of those patients have TT, compared to 81% of controls. Hence TT is the less risky version.

    The outcome of this study implies that C results in a down-regulation (or T in an up-regulation), since down-regulated VDR is associated with prostate cancer in general. The risk being present in those with the lowest vitamin D levels also supports this, since elevated vitamin D can result in the vitamin D receptors being more active even when VDR is dysfunctional - so the ones with higher D levels are essentially able to compensate somewhat for having slower VDR.

    Source [2] shows increased severity with TT, but not increased risk of acquiring the disease, so it's a rather weaker association, in addition to being outnumbered by the other studies.

    [1] http://www.nature.com/jhg/journal/v53/n3/full/jhg200825a.html
    Family-based analysis of vitamin D receptor gene polymorphisms and type 1 diabetes in the population of South Croatia
    We observed overtransmission of Tru9I allele G and undertransmission of the Tru9I-BsmI A-A haplotype from parents to affected children

    [2] http://www.ncbi.nlm.nih.gov/pubmed/23246977
    Genetic polymorphism of vitamin D receptor gene affects the phenotype of PCOS.
    Distributions of genotypes and alleles did not differ between cases and controls, indicating that this SNP is not associated with increased risk for PCOS. However, this SNP was found to be associated with the severity of the PCOS phenotype. In particular, presence of the A allele is associated with a 74% increased risk of severe phenotype development (OR, 1.74; 95% CI, 1.07-2.82).

    [3] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2675652/
    Vitamin D-related genes, serum vitamin D concentrations and prostate cancer risk
    Individual SNP analyses showed significant associations in men in the lowest tertiles of serum 25(OH)D with . . . 1.84 (1.19–2.86, P trend = 0.007) for rs757343 (IVS10+443A>G). . . .
    Table III: Bottom tertile = case/control ratio of 138/200 for AA, 61/48 for AG+GG.
     
  11. Valentijn

    Valentijn Activity Level: 3

    Messages:
    6,510
    Likes:
    9,640
    Amersfoort, Netherlands
    I've updated the list in the initial post to correct rs3847987, and to clarify that "TT" is protective for rs757343 since the common version is the riskier one.
     
    ukxmrv likes this.
  12. nandixon

    nandixon Senior Member

    Messages:
    125
    Likes:
    117
    Hi Valentijn,

    I think you're probably right with your analysis but one of the papers you cited, together with the following one, makes me think the rs757343 SNP may need to be looked at more situationally:

    In the study, "Protection from type 1 diabetes by vitamin D receptor haplotypes" (http://www.ncbi.nlm.nih.gov/pubmed/17130574), all of the VDR haplotypes containing the major C allele ("G" in the study) for rs757343 ("Tru 1" in the study) were protective against type 1 diabetes.

    And in your source [3], "Vitamin D-related genes, serum vitamin D concentrations and prostate cancer risk" (http://www.ncbi.nlm.nih.gov/pubmed/19255064), the minor T allele ("A" in the study) seems to be non-risk or risk with respect to prostate cancer risk depending on whether serum vitamin D levels are lower or higher, respectively.

    Based on all the studies then, it seems to me that the heterozygous genotype, CT, is actually "safest" overall, at least for the time being, and that individuals who are CC probably don't need to worry, especially if they have one of the favorable VDR haplotypes (approx. 80% of the population is CC anyway).

    I would actually be most concerned if I were a man with the TT genotype who was supplementing large amounts of vitamin D.

    In any event, I think many of the other VDR SNPs are more important than rs757343, either singularly or in combination, and most people probably don't need to worry too much about that one. :)
     
    Valentijn likes this.
  13. Valentijn

    Valentijn Activity Level: 3

    Messages:
    6,510
    Likes:
    9,640
    Amersfoort, Netherlands
    I think this is a pretty poor source, unless the (paywalled) full text has a lot more information in it. First of all, it's looking at haplotypes, which are a rather complicated interaction between multiple SNPs. Haplotypes also are generally discussed when no SNP was found to be statistically significant by itself. As an example, in that abstract the Taq-Apa haplotype is already protective, even without Tru being added onto the end. And without the full data, it's rather impossible to guess if Tru is actually contributing anything significant to the haplotype, much less whether Tru does anything in isolation from the haplotype.
    Actually this different level of risk depending on vitamin D status is extremely relevant - dysfunctional VDR functions much better when there's more vitamin D in the system. Hence having the risk only manifest at a statistically significant level when there's low vitamin D is a very strong indication that the allele is causing a down-regulation. And that down-regulation can be compensated for with vitamin D supplementation.
    I must disagree ... a down-regulation which responds to vitamin D, as suggested by [3], is a very strong indication that the SNP is relevant, and that taking steps to mitigate the problem (by supplementing vitamin D) is helpful.
     
  14. nandixon

    nandixon Senior Member

    Messages:
    125
    Likes:
    117
    I found some additional research (a Chinese/US collaboration from 2005) that supports your analysis that the T allele is protective with respect to rs757343 (Tru91):

    "Vitamin D receptor gene Tru9I polymorphism and risk for incidental sporadic colorectal adenomas" (Abstract: http://www.ncbi.nlm.nih.gov/pubmed/16097046; Full text: http://www.wjgnet.com/1007-9327/full/v11/i31/4794.htm)

    I read the entire full paper (since I have some interest in trying to prevent colon cancer), but here is a brief quote from the Abstract:

    "CONCLUSION: Our findings suggest that the VDR Tru9I polymorphism may be associated with lower risk for colorectal adenoma, particularly in interaction with various risk factors, but not with calcium or vitamin D."

    From the full paper, it looks as though having one T allele is as protective as having two. So I think I'd still prefer being heterozygous, CT (I'm CC). :)
     
    Valentijn likes this.
  15. roxie60

    roxie60 Senior Member

    Messages:
    1,686
    Likes:
    532
    Central Illinois, USA
    so is the list at the top now correct for which allele's are 'risk'? If so now it appears the VDR Taq and Bsm now seem to indicate no risk (-/-) or is this the -/- is actually bad issue?
     
  16. Valentijn

    Valentijn Activity Level: 3

    Messages:
    6,510
    Likes:
    9,640
    Amersfoort, Netherlands
    The list is up to date.

    Whether there's a risk depends on the allele - Taq G and Bsm T are the riskier versions. But it looks like the the risk associated with Taq and Bsm is rather small, with a possible exception when Taq and Bsm are not synonymous.
     
    roxie60 likes this.
  17. This does contradict the genetic Genie report, making me even more confused
    e.g FGG has me as +/+ for VDR taq rs731236 AA and they say
    "With COMT V158M + and a VDR Taq + status, the body may have further trouble tolerating methyl donors"

    Nut if taq GG is the risk (as above) does that mean VDR DOESN'T give me trouble with methyl donors?
     
  18. Bluebell

    Bluebell Senior Member

    Messages:
    392
    Likes:
    210
    Teeny, because these thread posts close to further editing after one week, and surely you will continue to have updates to make to the data you are presenting, have you considered posting this info in another way on this forum, such as perhaps in the "blog" area? Or I guess (I'm not sure) there may be a "wiki" area (I know Rich mentioned it in some of his posts), or maybe that has been closed?

    I'm wondering what to do with my thread that contains my list of methylation links because I can't edit the first post anymore (nor most of the rest of my posts there) and it's getting cumbersome to repost the whole list every couple of weeks. I don't know if putting it into a "blog" area might (I'm not sure) allow me to update it continuously, but then of course it wouldn't get any views whatsoever there.
     
  19. Bluebell

    Bluebell Senior Member

    Messages:
    392
    Likes:
    210
    I also call her Nut -- we mean it affectionately, don't we? :D

    Al, Genetic Genie used to say AA VDR Taq was -/- but they changed it in January to align their reports with Yasko's reports.

    Here is a thread on VDR and how it really isn't too concerning if you have the majority alleles of Taq AA: http://forums.phoenixrising.me/index.php?threads/the-great-vdr-taq-bsm-debate.24474
     
    Valentijn likes this.
  20. Valentijn

    Valentijn Activity Level: 3

    Messages:
    6,510
    Likes:
    9,640
    Amersfoort, Netherlands
    I can edit older ones if needed, due to being involved in some other (currently stalled) projects compiling information.
     

See more popular forum discussions.

Share This Page