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Interesting MTHFR Variations

Discussion in 'Genetic Testing and SNPs' started by Valentijn, Aug 2, 2013.

  1. Valentijn

    Valentijn Activity Level: 3

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    Here's MTHFR, in all it's glory. There are lots of missense mutations, which are underlined, bolded, and orange. I added very rare missense mutations to the list even if they don't have research, hence those have a "?" after the risk allele, since it's really just the rare allele and not associated with any risk thus far.

    I left out one of the Yasko SNPs, MTHFR 03 P39P, since the research only shows a non-significant impact. There were also a few SNPs associated with blood pressure only, but because it isn't clear how they effect the gene function (up or down regulation), or even what the risk is (is the higher or lower BP "normal"?), I've left those off the list for now.

    rsID.........NAME....RISK...ETC
    rs2184226....A3301G..C
    rs3737967....R492H...G....T is protective
    rs868014.....R728R...A?...very rare
    rs4846049....A372C...T
    rs35737219...T653M...A?...very rare
    rs2274976....R594Q...T
    rs45590836...M581I...TT
    rs2274974....G566E...T?...very rare
    rs1476413....G35A....T
    rs4846051....F435F...G
    rs1801131....A1298C..G
    rs3927589....E423D...A?...very rare
    rs12121543...G76T....AA
    rs121434296..R377T...A....i5003528
    rs267606886..W339G...CC...i5003529
    rs267606887..N324S...CC...i5003530
    rs121434297..L323P...G....i5003527
    rs1801133....C677T...A
    rs45550133...R134C...A?...very rare
    rs2066472....R68Q....T?...very rare
     
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  2. Valentijn

    Valentijn Activity Level: 3

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    So what is MTHFR and why is it important?

    MTHFR stands for methylenetetrahydrofolate reductase, and is the name of an enzyme and the gene which creates it. It creates the active form of folate (5-MTHF), which is necessary for lots of essential things. Being deficient can cause birth defects, elevated homocysteine, anemia, etc.

    Problems with MTHFR being downregulated can be treated by supplementing folate.
     
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  3. Bluebell

    Bluebell Senior Member

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    "rs3737967....R492H...G....T is protective"

    For this one, GG is very common - 90% of Europeans, 82% of Asians

    TT is in like .001 of people or something.
    Is even one T protective? That's not very common either - 7% European and African, 16-18% Asian.
    Not many population groups are listed for this SNP in dbSNP, why would that be?

    Why is G risky?

    ----
    I have a couple of the ones you said were "risky", but they are all shared with about 50% of the population. (I have none of the ones that you said were really rare.)

    Is the best way to find out why they are risky to look at Google Scholar (SNP)?

    ----
    When you just have one thingie (that's a technical term) listed in the "Risk" column, like an "A", does it mean that it's risky to be either homozygous or heterozygous, as long as one A is in the pair?

    ----
    When you said (on another thread) that you have presented these SNPs (in your series of reports here) in the order they would be listed when one is reading one's results, what results list are you talking about? The 23andMe data? I typed in MTHFR in the gene search box in my 23andMe data, but my results didn't look like your list in the first post.
     
  4. Valentijn

    Valentijn Activity Level: 3

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    Yes, even one T is protective. No idea why there's not much group data ... some SNPs don't have any at all.
    Because the research shows it is :p Basically the minor allele (T) results in statistically significantly lower homocysteine according to Table at of http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745176/ . By listing "MAF" it indicates that they're talking about the minor allele in the other data, which shows a negative "Beta" value indicating that the minor allele is causing lower levels rather than higher. It also shows a highly significant p-value for the result - basically 0.00000000000041 versus the 0.05 usually used as an upper limit to determine significance.
    Risk and prevalence are not necessarily related, hence a rare version can be more beneficial than the common version.
    Yup, though in the case of some missense mutations, etc, the position for the mutation (such as MTHFR 492) might bring up results in addition to what would be found by searching for "rs3737967". Searching from the NIH site can also bring up additional results (such as by hovering over the cyan result in the gene map on http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=rs3737967).
    Yes, it means that a study has shown the risk to be associated with the allele or both heterozygous and homozygous genotypes, rather than just the homozygous genotype. Though thus far being homozygous for the risk allele has always indicated a bigger impact - at least, when studies are big enough and the risk allele is common enough for a statistical impact.
    Yes, it should be in order in the 23andMe results. I thought I did one or two of the early ones backwards, but I checked MTHFR and it's in the correct order. It does skip over some of the 23andMe results, since they don't have any impact, and some are only referred to by their "i" numbers (provided in the "Etc" column above).
     
  5. ahmo

    ahmo Senior Member

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    @Valentijn I followed your link from a current thread re SNPs to this one. A few months ago I downloaded your program, but I can no longer remember at which point in the process I got stuck. Currently I've been bashing my brain to understand basics, I seem to be getting more confused, not less, about reading SNPs. Specifically, I have SNPtips installed in Firefox. It highlights rs numbers i have when they appear on a web page. In your post above, all but 4 are highlighted. When I mouse over them, I'm shown my variants. So, in the first 3, I have TT, GG, GG.

    The trouble is, SNPtips or not, I'm totally stuck in what to do with this info. I'm fine with my methylation panel translated by GeneticGenie, but I just don't seem to be able to comprehend anything beyond. Yesterday I was trying to extrapolate for myself what someone was saying about NOS1 and NOS2. I put them into the Promethease interactive, and I get a number of results. Is it always a negative when there are double letters, ie TT instead of a combination?? :confused:I think you did a pretty comprehensive post about all things SNP, can you link me to it? Thanks very much, ahmo
     
  6. Valentijn

    Valentijn Activity Level: 3

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    Maybe it's this: http://forums.phoenixrising.me/inde...monia-other-problems.34225/page-2#post-531925

    Basically many SNPs have variations (perhaps some people have a AG instead of an AA somewhere, for example) and sometimes variations have an impact on how the gene performs. Hence there can be a risk allele which causes that impaired gene function. Or both alleles can make no difference at all.

    So you never know if TT, CT, or CC is causing any problems just by looking at it. But somewhere someone might have conducted research to see if those variations are associated with gene function, and/or if they are associated with risk of some disease. Reading the research is really the only way to find out which allele or genotype is the risky one.

    And then you also have to read the research to find the effect size, if there is a risky allele. Sometimes it's a very very small increased risk of a disease, but sometimes it's a big impairment in how efficiently the gene functions. And rarely, the allele directly causes a disease.
     
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