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.

MTHFR levels are influenced by your genes. If you’ve gotten your genes sequenced, SelfDecode can help you determine if your levels are high or low as a result of your genes, and then pinpoint what you can do about it. If you’re sick and tired of guessing about your health, SelfDecode can help you find specific answers that conventional doctors/diagnostics may never uncover.

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 the transformation of folate to 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].

mthfr-677ct-1298ac

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 the risk of migraines. However, if this genotype did have migraines 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].

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 in 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

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 (methylcobalamin), 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 option:

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].)

Irregular Folate Levels?

If you have not yet tested your folate levels, I recommend that you ask your doctor to do it. If you already have your blood test results and you’re not sure what to make of them, you need to check out Lab Test Analyzer. It does all the heavy lifting for you. No need to do thousands of hours of research on what to make of your various blood tests.

FDA Compliance

The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition.

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