new-insights-into-depression-medications-and-lmethylfolate-14-638

All You Need to Know About MTHFR Genes/Polymorphisms (C677T, Rs1801133)

There is a lot of misinformation about MTHFR, even though there are a lot of studies on this gene. This post goes through the actual science of this gene and what conditions it’s associated with.

What is MTHFR?

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The MTHFR gene codes for an enzyme known as methylenetetrahydrofolate reductase or MTHFR.

MTHFR is responsible for converting 5, 10-methylene THF to 5-methyl THF, which is essential for the conversion of the amino acid homocysteine to methionine [R, R1].

This enzyme is very important for the production of DNA and methylation pathways that are essential for all bodily functions [R].

MTHFR plays a central role in transformation of folate to form S-adenosylmethionine (SAM), the universal methyl donor in cells and affects DNA methylation status.

A different post will deal with methylation in general.

The Two Main MTHFR SNPs

Genetic variations in the MTHFR gene results in reduced activity of the enzyme produced and have been associated with a series of diseases and conditions, including cardiovascular disorders, neurological defects, some forms of cancer, psychiatric disorders, diabetes, and pregnancy complications [R, R2].

The two most common MTHFR mutations (polymorphisms) found in humans are:

  • MTHFR C677T (Rs1801133). This mutation (the A allele) is associated with reduced enzyme activity, elevated total homocysteine levels and altered distribution of folate [R]. People with an “A” allele for this mutation present a 35% decrease of the normal enzyme activity and “AA” individuals a 70% decrease [R].
  • MTHFR A1298C (rs1801131).  This mutation also impacts the MTFHR activity and the homocysteine levels but to a lesser extent than C677T [R].

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The enzymatic activity of MTHFR in people with one minor allele in each MTHFR C677T and A1298C polymorphisms is lower than the activity present if each SNP separately had a minor allele [R].

Reduced MTHFR enzyme activity results in a decreased conversion of the amino acid homocysteine to methionine and accumulation of homocysteine in the blood. Abnormally elevated homocysteine levels are referred to as “homocystinuria” or “hyperhomocysteinemia” (Hhcy) [R].

The elevation of homocysteine levels in the blood may increase susceptibility to a series of diseases [R, R1]. 

A series of studies have linked MTHFR polymorphisms, especially the C677T, with various types of diseases but the results are sometimes conflicting and controversial. This can be attributed to a) small sample sizes and b) geographical factors that impact on the presentation of diseases in varying ethnicities or populations [R].

The various diseases that have been associated with MTHFR polymorphisms, especially C677T, are briefly presented below.

Diseases linked to MTHFR C677T mutations (the “A” allele)

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The C677T Polymorphism is associated with increased risk for the following conditions (assuming an A allele):

There is no study for my observations, but I noticed people with the A allele are more likely to have “lectin sensitivity.”

  • Strokes of various kinds in different populations [R, R1, R2, R3] and stroke in children [R]
  • Heart disease if lower folate levels [R]
  • High blood pressure (also GG of MTHFR A1298C) [R]
  • Male infertility especially in Asian populations (homozygous AA) [R, R1, R2, R3]
  • Depression [R] – high Homocysteine and dysfunction of methylation metabolic pathways are critical to the synthesis of noradrenaline and serotonin [R].
  • Autism spectrum disorders [R, R1, R2, R3]
  • Alzheimer’s [R, R1]
  • Dementia [R]
  • Parkinson’s [R, R1]
  • Multiple sclerosis but the evidence in controversial [R, R1, R2]
  • Rheumatoid Arthritis [R]
  • ADHD (A1298C) [R]
  • Migraines with or without aura [R, R1, R2] – A different study found that the “AA” genotype reduced risk of migraines..However, if this genotype did have migraine with aura, then the risk for cardiovascular disease was increased by 3.66X and 4x increased risk for ischemic stroke [R]
  • Diabetes and diabetic kidney problems (nephropathy) in patients with type II diabetes. The risks vary between Caucasian, Asian, Arabic and Chinese Han populations [R, R1, R2, R3].
  • Schizophrenia [R, R1]
  • Unipolar depressive disorder and bipolar disorder [R, R1]  
  • Cancer – It has been previously demonstrated that folate deficiency can increase the incidences of different forms of cancer. MTHFR is directly involved in folate metabolism and therefore MTHFR mutations may impact on the development of cancer [R, R1].
    • Prostate cancer [R, R1]
    • Ovarian cancer [R, R1]
    • Esophageal cancer [R, R1]
    • Stomach cancer [R, R1] – The “A” allele increases the likelihood that an H Pylori infection will cause stomach cancer [R].
    • Bladder cancer [R, R1]
    • Brain cancer [R]
    • Lung cancer [R]
    • Kidney cancer [R]
    • Head and neck cancer [R]
    • Colon cancer [R] – and more side effects from 5-fluoruracil treatment [R]
  • Hearing impairment [R]
  • Lower Bone Mineral Density in the spine and neck [R]
  • Cluster Headache [R]
  • Epilepsy [R]
  • Peripheral Arterial Disease [R]
  • Worse outcomes for end stage kidney disease [R]
  • Adverse effects of methotrexate in rheumatoid arthritis [R] and Increased liver toxicity from methotrexate (folate blocker) [R]
  • Recurrent pregnancy loss [R, R1]
  • Pre-eclampsia, a serious complication of pregnancy [R].
  • Having a Down syndrome kid if the mother has a mutation [R].
  • Neuronal tube defects (NTD) such as anencephaly and spina bifida in newborns [R].
  • Cleft lip and palate [R]
  • Lower Luteinizing Hormone [R]
  • Cataracts [R]
  • Alopecia Areata [R]
  • More severe Colitis [R]

Testing Homocysteine and Folate

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It should be noted that most of the studies done on MTHFR genes only show correlations with disease when homocysteine levels are high or folate levels are low.

Therefore, you want to get your homocysteine levels measured. This is easily done with a blood test that you can ask for from your doctor. High homocysteine levels show that you may have a methylation issue or a B12/ folate deficiency caused by a possible MTHFR mutation.

Decreasing the levels of homocysteine in the blood will reduce the risk for development of any of the disorders presented above. The intake levels of folate, vitamin B12 (cobalamin) and vitamin B6 (pyridoxal phosphate) affect the levels of homocysteine in the blood [R].

A vitamin-rich diet that includes fruits, vegetables, dark leafy greens (spinach, kale, bok choy, and Swiss chard), eggs and red meat provide the B vitamins needed to maintain the homocysteine levels low and closer to normal levels. Additionally, supplementation with all three vitamins, folate, B12 and B6, can normalize homocysteine levels [R].

Healthy control have a homocysteine under 7 μmol/l, whereas those with schizophrenia have 12 μmol/l [R].

Check:

Checking Your MTHFR SNPs

MTHFR is an enzyme which affects the methylation of all cells. Methylation is important for various biochemical conversions which determine the expression of your genes [R1].

For MTHFR C677T:

  • Each T allele= Lower methylation, higher homocysteine [R1]
  • TT=60–70% reduced MTHFR enzyme activity
  • CT=30–40% reduced enzyme activity, respectively, as determined by in vitro analysis of the MTHFR activity [R2,R3,R4].

SelfDecode has a list of SNPs is the MTHFR gene that are found on 23andme:

  1. RS1476413 (MTHFR)
  2. RS17367504 (MTHFR)
  3. RS17375901 (MTHFR)
  4. RS1801131 (MTHFR)
  5. RS1801133 (MTHFR)
  6. RS2066470 (MTHFR)
  7. RS2274976 (MTHFR)
  8. RS4846049 (MTHFR)
  9. RS4846051 (MTHFR)

Bioavailable vs Synthetic Folates

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It has recently been shown that the human gut can convert the folates from food sources to 5-MTHF (the type of folate that our body can use) very efficiently. However, its ability to convert supplemented folate is limited [R].

Reduced folate ((6S) 5-MTHF) is the bioavailable form of folate in the human body and is recommended for supplementation instead of the usual folate found at the drug stores [R, R1, R2].

Bioavailable forms of vitamins do not need to be processed in the body and can therefore be absorbed quickly.  Some patients, especially those who are double homozygous for MTHFR mutations, do not tolerate high doses. Therefore, you should advance the dose slowly.  Additionally, you can supplement with methyl-vitamin B12 (methyl-cobalamin), the bioavailable form vitamin B12, instead of the usual vitamin B12. This will make the access to vitamin B12 for your body easier.

You should also avoid taking high doses of niacin (vitamin B3), which can decrease methylation and therefore reduce the conversion of homocysteine to methionine and result in homocysteine accumulation.

Which Folate to Buy

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Folate is an important micronutrient in DNA synthesis, integrity, and stability.

You want to buy the folate that doesn’t require the MTHFR enzyme to convert, which is the methylfolate variety.

Be aware that some people don’t do well on methylfolate supplements.

Joe’s Favorite:

Other good options:

Folate Requirements

The minimum daily requirement of folate is 50 μg, although the current recommended intake is 400 μg/ day for the average adult. During pregnancy folate supplementation needs to be increased to 600 μg/ day [R].

(Keep in mind that folate supplementation is known to mask anemia caused by insufficient levels of vitamin B12 [R].)

Comments

  1. Vicki Muldrow

    What happened to my post that reads:
    Hi Joe! Forgive me if this is a double post, the first one said the connection was reset. Anyways, I have read mostly your articles about my DNA and I could really use some help. I have confusing info. So, here’s my mix
    DRD2 TAQ1A AA report says low dopamine receptors
    VAL158MET AA report says low COMT
    CYP2C9 Intermittent metabolizer
    CYP3A5 “”””
    MTHFR BOTH 1298A C AA You mentioned Val158met as a bad mix
    AND 677C. T TT

    From a psychiatric standpoint do I need to increase or decrease dopamine? Is there a homeopathic solution to these genotype problems? Am I a movie title or curable?

    I would really appreciate some input, as when I put the articles together, they don’t work. There doesn’t seem to be a low Comt and Low Dopamine option. Anywhere. I feel low dopamine but the met is AA, that means high right?

    Anyways, I know this is messy but if you could try to help me out?

    Thanks,
    Vicki

    • Natcha M

      Hi Vicki,
      First of all, the SNPs can tell if you have a genetic tendency to something, but it doesn’t mean you will absolutely have the problems. Gotta look at the whole person and the environment as well. You can’t cure your SNPs but you can manage your environment and nutrition. If you want some help answering individual questions or genetic consulting, you can book an appointment with Joe here: https://selfhacked.com/contact/. ~Natcha @ Team SelfHacked

      • Vicki Muldrow

        Thank you. I am aware that these are potentials. Let’s just thank whoever, that my teachers were always complaining that I don’t live up to my potential.

        I have sent Joe an email.

  2. Vicki Muldrow

    Hi Joe! Forgive me if this is a double post, the first one said the connection was reset. Anyways, I have read mostly your articles about my DNA and I could really use some help. I have confusing info. So, here’s my mix
    DRD2 TAQ1A AA report says low dopamine receptors
    VAL158MET AA report says low COMT
    CYP2C9 Intermittent metabolizer
    CYP3A5 “”””
    MTHFR BOTH 1298A C AA You mentioned Val158met as a bad mix
    AND 677C. T TT

    From a psychiatric standpoint do I need to increase or decrease dopamine? Is there a homeopathic solution to these genotype problems? Am I a movie title or curable?

    I would really appreciate some input, as when I put the articles together, they don’t work. There doesn’t seem to be a low Comt and Low Dopamine option. Anywhere. I feel low dopamine but the met is AA, that means high right?

    Anyways, I know this is messy but if you could try to help me out?

    Thanks,
    Vicki

  3. Kelly Patel

    Hi Joseph,

    I recently found out I have an MTHFR C677T mutation as well as COMT mutations. Both are homozygous. I am about 6 weeks pregnant and have been taking methylfolate and methyl b12, but have been experiencing side effects (mostly extreme anxiety). In the past, I have had high blood levels of folate. Do you have any experience with this type of issue? I know I need methylfolate for a healthy pregnancy, but I also know the COMT mutation makes it very difficult for my body to handle methyl groups. Just curious if you have any thoughts on this!

    Thanks so much

  4. Erin Umberg

    Great post, love reading your blog as someone who used to be in research.
    A quick question of clarification, you discuss the mutation gene MTHFR C677T with the A allele conferring lower enzyme activity, then lower in your post you talk about this same gene with “T” allele. I thought it was either A or G allele for C677 (which corresponds with snp rs1801133), is that incorrect?
    If MTHFR C677T corresponds with snp rs1801133, why does 123andme say there are only A or G variants whereas in your post (and elsewhere), I’m seeing T/C variants. Could you clarify further?
    Thank you!

  5. Doug

    According to some, homocysteine testing is only meaningful if you do a methionine challenge: test after fasting, do a methionine load, test again 4 hours later.

    • DK

      This was a decent post. Being homozygous MTHFR C677T and COMT V158 along with a variety of others makes me wonder what I’d have been like if I’d addressed the SNPs 50 years ago. Add on a mouthful of amalgams since I was 5 y.o. that I couldn’t detox well due to these SNPs and it’s a wonder I’m not in bad shape. My son has the same SNPs and he’s got some challenges for sure. Of course, you can’t look at MTHFR in isolation. There are lots of people homozygous MTHFR, so its not exactly a death sentence. The people that had a bad reaction to 5-MTHF unfortunately started with too high a dose for them. Their body also stresses to it even when they need it. My wife had a hard time when I went from 1mg/day 5-MTHF to 1.3mg of Quatrefolic. If your B12 is low, that obviously doesn’t help. I don’t think plasma B12 levels are reflective of availability.

      No need to rag on Ben Lynch. His website is ok for general info. If you really want to get deep in the weeds with methylation you can read some of Dr. Amy Yasko’s free books and papers. Unfortunately, her protocols are overly complicated and she pushes her own proprietary supplements pretty aggressively. In fairness, some are very specialized and concentrated and the prices are ok for most.

  6. Personally I find niacin highly worthwhile with one polymorphism on the C667 SNP. It upregulates BDNF, which is in itself one of the reasons why I run. It is also a precursor to NAD and NADP which might explain why it motivates me.

    Here is the thing, every day I wake up, and I think of this site, because I run into a conflict.

    When I wake up I have an empty stomach (which matters for almost every supplement and no one ever talks about) and I have to begin taking supplements. I take niacin on an empty stomach because if I don’t then it doesn’t feel like it works, I am convinced that flushing does something. I also take SAM-e and longvida curcumin.

    But you also say to take resversatrol first thing in the morning because it gives you extra energy. I am confused to which order these should go in, and which need to go in alone. How can I get the maximal benefit from these four supplements: SAM-e, niacin, resversatrol and longvida curcumin? I am guessing resveratrol comes last, since the niacin will be converted into niaciamide? Should SAM-e go in by itself or is it OK going in with the niacin and longvida? About to step out and buy methylfolate and methyl b12.

    SAM-e is the most powerful supplement I’ve taken in my life, followed by longvida curcumin. I’ve been interested in resveratrol since I was 16, I am not sure why I can’t feel it like I feel the others. Is it because it needs an empty stomach? I really do think of this every single morning.

  7. Rich

    I had the worst reaction of my life using this supplement. I had panic attack and huge anxiety, before I never had any psychiatric condition.

  8. Santino

    Why do you think anybody should take Methylfolate Joseph?

    Did you check out the studies about how b vitamins work at lowering homocysteine?

    Most of them use folic acid (often in combination with cyanocobalamine and b6) and folic acid is very effective at lowering homocysteine, even in people with one Allele C677T. People with 2 Alleles also reacted positive, however their folate levels did not rise as high as by people without the “bad” mutation or those who had only one Allele.

    I did research up until April 2016 and in my opinion there is no need to take Methylfolate.

    But if you are homozygous C677T, you should only take low amounts of folic acid like for example 100mcg. On a regular basis this is sufficient, especially with a diet rich in vegetables or fiber like inulin (as folate is also significantly produced by bacteria).

    I also think that the intermediate forms that it builds (folic acid) also have functions which L-Methylfolate cannot fulfill. So I would say use small amounts of folic acid and eat leafy greens if you are homozygous.

    If you have a single c667T mutation or no mutation at all, you are fine with folic acid. So most of the people are. In the studies they found 1mg daily to be most effective for lowering homocysteine. Higher intakes had no further benefit and lower intakes did not have as much benefit. However if you only prevent disease, I guess 100-200mg folic acid are sufficient if you wont only eat crap.

    So far, there is no evidence that Methylfolate has any benefit over folic acid. I even see more disadvantages compared to folic acid (not well studied–>risks; costs and side effects). Only homozygous C677T might benefit, but this has to be researched before you may use the word “should”.

    So I really do not understand why you advice anybody to take Methylfolate, because you claim, that you practice evidence based. This is quite speculative.

    Maybe you should wait until studies have shown real benefits (which go beyond the effects of folic acid).

  9. Rael

    There are tons of people getting horrible side effects from methyl folate, and these effects lasts weeks, sometimes months. At first I couldn’t believe, but reviews from this supplements are appearing a lot in some forums. I don’t know the reason, but it seems very very dangerous. I wouldn’t risk.

    • Holly

      one of the main reasons for the Rael, is that people may be “methyl trapping”. There has to be enough B12 on board FIRST before adding the methyl folate. One probably needs some lithum on board too in order to drive the B12 into the cells. A good practitioner would know and recognize this and adjust accordingly.

    • Joseph M. Cohen

      Probably lower cancer risk. Maybe also helped in low B12 environments (in cases of more plant based diets, where folate is high and B12 is low).

  10. Henrik

    Joe,

    you have been “lynched”.

    It is not true that the active folate is better than folic acid. in practice there are lots of report from people with homozygous mthfr c677t who had high homocysteine and brought into the normal range with folic acid.

    I an compound heterozygous and 400mcg of folic acid in a regular b complex were sufficient to keep my homocysteine low. even though it was all ok with my homocysteine (had high folate levels due to folic acid supplementation) I stopped taking all supplements when I read that I should not take folic scid with my mutation from Dr. Ben Lynch.

    After 8 months without supplements, but instead eating leafy greens daily, my homocysteine ended up at 50!!

    I am taking folic acid 1mg daily now to lower it again. By the way you have been lynched as the graphic above is what is pushing Dr. Ben Lynchs supplement shop. Folic acid has lots of useful properties which it demivers over and over again when it is tranformed into different folaes.

    I can post on that later in more detail if appreciated.

    0.5-1 mg folic acid daily is sufficient for most people and if not, it is not as simple as saying homozygous c677t is the cause.

    On phoenix nutrition there is a patient report from somebody with a homozygous c677t mutation and a homocysteine of above 90, that he lowered into normal range with just folic acid and hydroxocobalamine and very low doses of b2 and b6.

    Also regarding the b12: No Methylcobalamine is not the best form in my opinion. The most natural form which the body can convert in his own speed and that is the form most common in food is hydroxocobalamine.

    Studies about b vitamins and homocysteine have shown that even cyanocobalamine is very effective and that hydroxocobalamine is little more effective and especially faster effective in restoring mma, homocysteine and b12 levels.

    • Joseph M. Cohen

      Synthetic folate can decrease NK cell toxicity, that’s why I don’t recommend it. I am not saying it can’t bring down homocysteine.

      • Henrik

        In this article I don`t read anything about the NK cells and folic acid. Did you check whether methylfolate does not inhibit NK cells? Because when people ingest 1mg or less, the folic acid is converted in the liver directly, so I would wonder if there is a NK inhibition in that case…

  11. Sebastian Achter

    Hey, great article;) I really like to read your articles in my spare time. My B12 (Cobalamin) and Folate levels are elevated, doctor’s dont know why ; I’m just checking my homocystein levels to see if there’s a problem. My Organs are fine and my doctor excluded a major disease; but i really feel tired and have brain fog, on some days more, on some days less. Do you think that TMG(Now Foods) and SAM-e could help me if my homocystein is not in range? Is SAM-e even necessary?
    I also fixed my diet 1 year ago according to some of your suggestions and it made a big difference, I really feel better and can work again. Before I was insulin resistant and could barely walk. Doctor’s in my country don’t know sh*** about Methylation, so it’s me and the internet;)

    Thank you so much!
    Best regards

  12. WOW, this is fantastic! I have a double mutation gene of the MTHFR C677T. This helps me to understand it all better and the importance of my supplements.
    I am wondering though… I will pass this to my children, right? Should they be taking a supplement as well??
    Thanks for all you do SelfHacked!

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