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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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    Northcoast NSW, Australia
    @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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  7. TheChosenOne

    TheChosenOne Senior Member

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    All the SNPs that I could find were the good ones, except for rs3737967 for which I have the normal GG variant and C677T (AG).
    Does that mean that the C677T mutation I have is not really a problem?
     
  8. Valentijn

    Valentijn Activity Level: 3

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    It probably isn't. Being heterozygous for it reduces MTHFR enzyme activity to about 65% of optimal. But because C677T and A1298C mutations are extremely common, normal people have MTHFR enzyme activity only slightly higher than that on average, at 70% of optimal.

    The only time I'd take it seriously is if homocysteine is elevated, or during pregnancy, when a mother having those mutations results in increased odds of neural tube defects in the fetus. But even then, it would only warrant a normal (400-800mcg) dose of folate, and/or a diet with a decent amount of vegetables.
     
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  9. MrME/CFS++

    MrME/CFS++

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    Hi @Valentijn !

    So, I got this MTHFR "rs35737219...T653M...A?...very rare" mutatin poping up in your Genes Analysis Software! Thanks by the way!! For the software I mean, not for giving me rare genes. :D

    I also got MTHFR C677T and A1289C hetero. Unknown if its compound or not, or if that is important at all!. It also shows up an rare variant of MTHFR rs1057624 in GA report. Does this all together say something to you? Lots of stuff going on in my MTHFR gene! Thats for sure. :p
     
    Last edited: Feb 16, 2016
  10. Valentijn

    Valentijn Activity Level: 3

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    There's been one research paper on the MTHFR T653M SNP, rs35737219, which showed a null result for it. Unfortunately it was a study involving eye problems, which isn't a particularly useful place to look for the impact of MTHFR mutations. Results for all of the other MTHFR SNPs were also null in that study.

    The amino acid substitution rates -1 on a BLOSUM62 chart, which means the two amino acids are fairly different. Hence it might cause some alteration in functionality. But it doesn't seem to be in a particularly important location on the protein, so might have no effect at all. Basically ... no one knows if it does anything yet :p
     
    Last edited: Feb 17, 2016
  11. MrME/CFS++

    MrME/CFS++

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    Lets hope so! ;)
     
  12. Flo

    Flo

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    I am confused about a few things you said.

    You said "C677T and A1298C mutations", but I think those are not mutations, but polymorphisms.Isn't there a big difference? I am pretty sure from my readings that mutations turn into polymorphisms if they have a null or favorable effect on survival. And a mutation will not be common, by definition, am I right?

    Also, could homocysteine be low and someone can have a high functioning MTHFR gene?
     
  13. Valentijn

    Valentijn Activity Level: 3

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    "Mutations" technically covers every permanent change in DNA. It can even apply to changes where there is no difference at all in the amount or form of the protein produced, in the case of "silent mutations". Mutations are accordingly very common. They don't have to be new, or uninherited - those types have different labels.

    But people tend to think "mutations" means the change is important or at least fairly significant, so it can be confusing to use that terminology for changes which have no impact at all. In that case, "variant" or "variation" seems to get the point across, whereas "polymorphism" is going to confuse a lot of people (and has a more specialized meaning).
     
  14. Flo

    Flo

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    Even with all the debate going on now in this terminology I do not read anywhere that a mutation would occur over 1% of the time in a specific population. See "Defining “mutation” and “polymorphism” in the era of personal genomics". Up until now a mutation in a population was considered to be any change that is in less than 1% of the population. That cutoff is arbitrary, but It is the uncommonness that is the defining characteristic of a mutation in a specific population(1)(2). Mutations in population genetics are by definition never "very common". That would mean that one could not call C677T a mutation in general, since in the Caucasian population it occurs over 1% of the time.

    Maybe you meant to use "variant" instead of "mutation"? They are all variants, but in specific populations they could be either a mutation or a polymorphism as is the case with sickle cell disease.

    So a mutation is a rare variant in a specific population, while a polymorphism is a common variant in a specific population. Both of which may or many not lead to disease.

    PHEW! Now I think I have it.

    Polymorphism is still useful when looking at a population and should not be confusing if we understand what it means. See here:
    https://books.google.com/books?id=pBq69Luwf7UC&pg=PA104#v=onepage&q&f=false

    By calling C677T and A1298C "mutations" instead of variants I am afraid you confused me! :) In MY population, they are less confusingly called polymorphisms or variants and they would never be called variants.

    Will you agree to this as a good set of definitions going forward?
    Variants occur in all populations and includes mutations and polymorphisms.
    Mutations are variants that occur in less that 1% of the time in a specific population.
    A Polymorphism are variants that occur in over 1% of the time in a specific populations.
    Mutations and polymorphisms may or may not be pathenogenic in any specific population.

    Since the debate is still going on in people way smarter than us, I think it would be great for the time being if we can agree on our own vocabulary so we can start feeling better!
     
  15. Valentijn

    Valentijn Activity Level: 3

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    Well, that's the definition of one group. It hasn't made it into wikipedia, or anywhere else that most people are likely to look. Are you (and they) suggesting that "missense mutations" should be relabeled as "missense SNPs" simply based on a lack of rarity? Somehow it doesn't seem very practical.
    No, for a forum on a website which is not aimed at genetic discussions, I think it's best to use the terminology which people with no genetic background can understand. More technical language has its place in research and academic discussions where extremely disabled people won't have to learn an entirely new vocabulary to ask a simple question.
    Vocabulary isn't going to cure anyone. And I don't feel any need to demonstrate an ability to mimic the "way smarter" people.
     
  16. Flo

    Flo

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    One group? I do not know what you mean, these are geneticists, it is in textbooks on genetics.

    ..and it is on wikipedia:
    https://en.wikipedia.org/wiki/Polymorphism_(biology)#Genetics

    I have a feeling they are changing a lot of the vocabulary. But I am suggesting we keep it as it has been so we can have a clear conversation about this.

    Polymorphism and single nucleotide polymorhism (SNP) are not interchangeable terms. You seem to be using them interchangeably. Not all single-nucleotide changes are SNPs, some are single nucleotide mutations since they do not occur in over 1% of the population. To be classified as a SNP, two or more versions of a sequence must each be present in at least one percent of the general population(1). (I hope you can see the foot notes I am using)

    So a SNP is any variant caused by a mutation in a single nucleotide that is present in over 1% of the population. This would rule out mutations like insertions, deletions, nonsense and frame-shifts turning into SNPs since they either remove nucleotides or change several of them.

    A missense mutation is a specific type of point mutation, but it is still a single nucleotide change. So I guess, yes, a missense polymorphism could be accurate because a polymorphismis (per current definiution) is only a point mutation that has found its way into a larger (>1%) population.

    These are you opinions. But your opinions do not mimic your actions. Your first post started by showing people missense mutations in the MTHFR gene. Then you go on to say "Basically many SNPs have variations". so what are you talking about SNPs or missense mutations? So are "C677T and A1298C mutations" or are they polymorphisms. That is not only complicated, but confusing as well. Missense mutaions is complicated on its own

    I think your lack of clarity might confuse people, and since you are making gene analysis software I was expecting more clarity.

    "Vocabulary isn't going to cure anyone." is a very simple and demeaning thing to say to my comment, which was inclusive and positive. A common vocabulary is the basis for understanding, understanding is the basis of knowledge, and knowledge is the foundation of discovery. You seem to be taking an antagonistic attitude toward me where I am trying to find common ground. I hope we can become sisters in this struggle instead of enemies.

    I think if we just call them all variants, and take into account the rarity of the variant and the research associated with it we can help simplify things for people who do not understand this at our level.

    So would you agree with wording things like this?
    MTHFR C667T is a common variant (polymorphism) in the Caucasian population that effects folate metabolism.
    MTHFR R728R is an uncommon variant (mutation) in the Caucasian population that has effects folate metabolism.(1)
     
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  17. Valentijn

    Valentijn Activity Level: 3

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    As I said above, insisting upon the use of such vocabulary is going to induce a lot of confusion for the lay-people using this forum, with no particular benefit. I'm going to understand what someone is saying regardless of whether they use "SNP" or "mutation" or whatever else.

    This is not a class room. The primary purpose in communicating is to be understood by the audience, and that is the factor which directs my usage of the vocabulary.
     
  18. Flo

    Flo

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    This is a place where people come to learn so it is a classroom for many people, including me. Maybe, it seems, you might think you are the teacher? You seem to be referring to people here as your audience. Regardless, you are not communicating to me, so you have failed by your own definition. I was trying to be helpful. It is not that I care about the vocabulary, I care that you might be using the vocabulary wrong. That is what will confuse people.

    When you say "Basically many SNPs have variations...", that is incorrect. Here is the definition of a SNP:
    A single nucleotide polymorphism is a variation in a single nucleotide which may occur at some specific position in the genome, where each variation is present to some appreciable degree within a population (e.g. >1%).[1]

    So, you actually just wrote "many variations have variations"! It just shows that if you do not even have a basic understanding of the vocabulary and maybe you should be a bit more humble regarding your knowledge about the subject in general.

    Are you a geneticist? Is that why you are referring to people who come here as lay people? Do you assume you have more knowledge than anyone else who comes here? If so, what are your credentials? Until then you are not my teacher, just another random person on the internet who might or might not know what they are talking about.

    I think you have a lot to offer, I hope you can think others have a lot to offer as well.
     
  19. Valentijn

    Valentijn Activity Level: 3

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    Of course I'm not a teacher. Which is why I frequently recommend taking online courses (such as Coursera) when someone wants to learn more about genetics, or is developing a flawed theory involving genetics.

    Any time you write anything, you should be considering your audience. Writing is pointless if it fails to put your arguments or information across in a manner which is comprehensible to the people reading your post.
    When most people on this forum (i.e., the people I'm trying to communicate with) say or hear "SNP", they are not thinking "a variant present in at least 1% of the population". They're not even thinking "Single Nucleotide Polymorphism". They're referring to a specific rs number, or i number, from their 23andMe results.
    No, I'm referring to us as lay people because none of us are geneticists, and most have a shallow and passing interest in genetics. Few people are concerned with learning enough to pass a genetic vocabulary test, and I dare say they would go elsewhere for more in-depth and precise definitions if that is what they are looking for.

    Will you be checking all posts made years ago to make sure they are accurate enough to suit you?
     
  20. Flo

    Flo

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    I am your audience. Your writing is not only incomprehensible, but wrong. It might be that most of the audience here does not have the ability to see why you are wrong. I do.

    But here again, you seem to want to teach me how to write to an audience. You play the role of a teacher even when you say you are not one.

    By definition a SNP can never be a mutation (in a specific population), nor a mutation a SNP. You still do not understand that and that is why you do not correct people, but instead of correcting them you want to continue their mistake because you think they will not be able to understand it?

    When I talk to people about this and they have an allele that is less than 1% in their population, I call it a mutation. I would say "your rs000000 mutation", not "your rs000000 SNP".

    The reason for this has several justifications. One is that a mutation can be either somatic or germline. Germiline meaning it is inherited, somatic mean that it was acquired from environmental exposure. A polymorphism is never the result of a somatic mutation.

    That last sentence was just antagonistic, demeaning, and unfriendly. I have only looked at your more recent posts in this forum on genetics, where I hope people who come here would be interested in genetics or learnig about genetics and how they might relate to or illness.

    Even though you seem to think "most people here" are a certain type, I am not that type. Yet, you cannot even seem to, or want to, agree with me on vocabulary, but rather, try to obfuscate for reasons I cannot fathom. I have a degree in the sciences, not genetics, but this is not what collaboration looks like.
     

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