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What are MTHFR Genes/Polymorphisms (C677T, Rs1801133)

Written by Joe Cohen, BS | Reviewed by Nattha Wannissorn, PhD (Molecular Genetics) | Last updated:

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MTHFR

The MTHFR gene is very important for DNA production & many bodily functions. Find out the REAL science behind MTHFR including how to check your SNPs.

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 [1, 2].

This enzyme is very important for the production of DNA and methylation pathways that are essential for all bodily functions [2].

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 [3, 4].

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 [1]. People with an “A” allele for this mutation present a 35% decrease of the normal enzyme activity and “AA” individuals a 70% decrease [5].
  • MTHFR A1298C (rs1801131). This mutation also impacts the MTFHR activity and the homocysteine levels but to a lesser extent than C677T [1].

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 [6].

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) [4].

The elevation of homocysteine levels in the blood may increase susceptibility to a series of diseases [3, 4].

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 [2].

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 [7, 8, 9, 10] and stroke in children [11]
  • Heart disease if lower folate levels [12]
  • High blood pressure (also GG of MTHFR A1298C) [13]
  • Male infertility especially in Asian populations (homozygous AA) [14, 15, 16, 17]
  • Depression [18] – high Homocysteine and dysfunction of methylation metabolic pathways are critical to the synthesis of noradrenaline and serotonin [19].
  • Autism spectrum disorders [20, 21, 22, 23]
  • Alzheimer’s [24, 25]
  • Dementia [26]
  • Parkinson’s [24, 25]
  • Multiple sclerosis but the evidence in controversial [27, 28, 29]
  • Rheumatoid Arthritis [30]
  • ADHD (A1298C) [31]
  • Migraines with or without aura [32, 33, 34] – 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 [35]
  • Diabetes and diabetic kidney problems (nephropathy) in patients with type II diabetes. The risks vary between Caucasian, Asian, Arabic and Chinese Han populations [36, 37, 38, 39].
  • Schizophrenia [40, 41]
  • Unipolar depressive disorder and bipolar disorder [40, 41]
  • 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 [2, 42].
    • Prostate cancer [2, 42]
    • Ovarian cancer [2, 42]
    • Esophageal cancer [2, 42]
    • Stomach cancer [2, 42] – The “A” allele increases the likelihood that an H Pylori infection will cause stomach cancer [43].
    • Bladder cancer [2, 42]
    • Brain cancer [44]
    • Lung cancer [45]
    • Kidney cancer [46]
    • Head and neck cancer [47]
    • Colon cancer – and more side effects from 5-fluorouracil treatment [48]
  • Hearing impairment [49]
  • Lower Bone Mineral Density in the spine and neck [50]
  • Cluster Headache [51]
  • Epilepsy [52]
  • Peripheral Arterial Disease [53]
  • Worse outcomes for end-stage kidney disease [54]
  • Adverse effects of methotrexate in rheumatoid arthritis [55] and Increased liver toxicity from methotrexate (folate blocker) [56]
  • Recurrent pregnancy loss [57, 58]
  • Pre-eclampsia, a serious complication of pregnancy [59].
  • Having a Down syndrome kid if the mother has a mutation [60].
  • Neuronal tube defects (NTD) such as anencephaly and spina bifida in newborns [61].
  • Cleft lip and palate [62]
  • Lower Luteinizing Hormone [63]
  • Cataracts [64]
  • Alopecia Areata [65]
  • More severe Colitis [66]

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 [4].

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 [4].

The healthy control group had homocysteine under 7 μmol/l, whereas those with schizophrenia had 12 μmol/l [67].

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 [2].

For MTHFR C677T:

  • Each T allele= Lower methylation, higher homocysteine [2]
  • TT=60–70% reduced MTHFR enzyme activity
  • CT=30–40% reduced enzyme activity, respectively, as determined by in vitro analysis of the MTHFR activity [68, 69, 70].

Check the SNPs out on SelfDecode:

  1. RS1801131 (MTHFR)
  2. RS1801133 (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 [71].

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 [72, 73, 74].

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 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.

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 [4].

(Keep in mind that folate supplementation is known to mask anemia caused by insufficient levels of vitamin B12 [75].)

Joe’s Favorite:

Other good option:

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.

Irregular Folate Levels?

LabTestAnalyzer helps you make sense of your lab results. It informs you which labs are not in the optimal range and gives you guidance about how to get them to optimal. It also allows you to track your labs over time. No need to do thousands of hours of research on what to make of your lab tests.

This post contains links from our sister companies, SelfDecode and LabTestAnalyzer. The proceeds from your purchase of these products are reinvested into our research and development, in order to serve you better. Thank you for your support.

About the Author

Joe Cohen, BS

Joe Cohen won the genetic lottery of bad genes. As a kid, he suffered from inflammation, brain fog, fatigue, digestive problems, anxiety, depression, and other issues that were poorly understood in both conventional and alternative medicine.Frustrated by the lack of good information and tools, Joe decided to embark on a journey of self-experimentation and self-learning to improve his health--something that has since become known as “biohacking”. With thousands of experiments and pubmed articles under his belt, Joe founded SelfHacked, the resource that was missing when he needed it. SelfHacked now gets millions of monthly readers.Joe is a thriving entrepreneur, author and speaker. He is the CEO of SelfHacked, SelfDecode and LabTestAnalyzer.His mission is to help people gain access to the most up-to-date, unbiased, and science-based ways to optimize their health.
Joe has been studying health sciences for 17 years and has read over 30,000 PubMed articles. He's given consultations to over 1000 people who have sought his health advice. After completing the pre-med requirements at university, he founded SelfHacked because he wanted to make a big impact in improving global health. He's written hundreds of science posts, multiple books on improving health, and speaks at various health conferences. He's keen on building a brain-trust of top scientists who will improve the level of accuracy of health content on the web. He's also founded SelfDecode and LabTestAnalyzer, popular genetic and lab software tools to improve health.

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