MTHFR

The MTHFR gene codes for methylenetetrahydrofolate reductase (MTHFR). MTHFR is an enzyme that activates folate (vitamin B9) [R]. 

Active folate helps convert toxic homocysteine to methionine, an amino acid used to make many proteins in the body. Methionine is also a precursor to S-adenosylmethionine (SAM-e) [R].

The MTHFR gene is involved in [R, R, R]:

• DNA production
• Methylation (a process that controls the activity of genes)
• Red blood cell production
• Brain health
• Heart health

The most common MTHFR polymorphisms are [R]:

• rs1801133: The ‘A’ allele is associated with reduced enzyme activity. This may lower folate levels and increase homocysteine levels.
• rs1801131: The ‘G’ allele is associated with reduced enzyme activity (to a lesser extent than rs1801133).

These variants have been linked to many conditions, such as neural tube defects, heart disease, and cancer. However, some studies have reported inconclusive findings [R, R, R, R, R]. 

The link between the ‘A’ allele at rs1801133 and neural tube defects is stronger. Folic acid supplementation may reduce the risk of neural tube defects in people with this variant [R, R, R].

The MTHFR gene provides instructions for making an enzyme called methylenetetrahydrofolate reductase. This enzyme plays a role in processing amino acids, the building blocks of proteins. Methylenetetrahydrofolate reductase is important for a chemical reaction involving forms of the vitamin folate (also called vitamin B9). Specifically, this enzyme converts a molecule called 5,10-methylenetetrahydrofolate to a molecule called 5-methyltetrahydrofolate. This reaction is required for the multistep process that converts the amino acid homocysteine to another amino acid, methionine. The body uses methionine to make proteins and other important compounds.

The MTHFR gene codes for an enzyme known as methylenetetrahydrofolate reductase, or just ‘MTHFR’ for short.

This enzyme is very important for the production of DNA and methylation pathways that are essential for all bodily functions [R]. MTHFR is responsible for converting 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate which is essential for the conversion of the amino acid homocysteine to methionine [R, R1].

Interpreting your MTHFR gene SNPs

The two most important SNPs you should look for are rs1801131 and rs1801133 .
Ofthe two, rs1801133 is more important.

First, take a look at your genotype for rs1801133:

• MTHFR CC677 (rs1801133) or GG is normal
• MTHFR C677T (rs1801133) or AG may reduce MTHFR function by 30% maximum (not so bad) 
• MTHFR 677TT (rs1801133) or AA may reduce MTHFR function by up to 70% (bad) 

So if you see “AA” in your file, this means your MTHFR enzyme activity is more likely not to function as well. AG means it still may not function as well, but the chances are lower. And finally, GG is the normal version and doesn’t impact this enzyme.

Next, take a look at rs1801131. This SNP has less of an effect on MTHFR function, but can still be useful to look at. For this SNP:

• MTHFR AA1298 (rs1801131) or TT is normal   
• MTHFR A1298C (rs1801131) or GT may slightly reduce MTHFR activity (not so bad)
• MTHFR 1298CC (rs1801131) or GG may reduce MTHFR activity more (bad)

For this SNP, GG could be the worst combination, but still doesn’t have a large influence overall.

To get a complete picture, look at your genotype for these SNPs together. If you have the “bad” genotype for both, the chances are higher that your MTHFR enzyme will not work as well. The least fornunate combination is MTHFR 677TT/ rs1801133 AA and MTHFR 1298CC/rs1801131 GG.

To learn more, take a look at this SelfHacked post. We also have a full report dedicated to the MTHFR gene on SelfDecode!

In more detail, the two most common MTHFR mutations (polymorphisms) found in humans are:

•         MTHFR C677T mutation at nucleotide 677, which substitutes a valine for an alanine at amino acid 222. This mutation is associated with reduced enzyme activity, elevated total homocysteine levels and altered distribution of folate [R]. People heterozygous for this mutation present a 35% decrease of the normal enzyme activity and homozygous individuals a 70% decrease [R].
•        MTHFR A1298C mutation, which substitutes a glutamate for an alanine at amino acid 429. It also impacts on the MTFHR activity and the homocysteine levels but to a lesser extent as opposed to C677T [R].

The enzymatic activity of MTHFR in double heterozygotes for MTHFR C677T and A1298C polymorphisms is lower than the activity present in each variant separately [R]. Reduction of the 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 mutations

•         The C677T polymorphism has been linked to an increased risk of developing haemorrhagic or ischaemic stroke in different populations [R, R1, R2, R3].
•         The C677T polymorphism has also been associated with ischaemic stroke in children [R].
•         Individuals homozygous for the C677T polymorphism who also have low folate levels have a higher risk for developing heart disease [R].
•         Homozygosity of MTHFR C677T mutation has been linked to male infertility especially in Asian populations [R, R1, R2, R3].
•         C677T polymorphism has been associated with recurrent pregnancy loss [R, R1] and the increase of the risk of pre-eclampsia, a serious complication of pregnancy [R].
•         Maternal polymorphism of MTHFR C677T is a risk factor for Downs syndrome in offspring [R].
•         Polymorphisms of the MTHFR gene have been associated with neuronal tube defects (NTD) such as anencephaly and spina bifida in newborns [R].
•         The MTHFR C677T polymorphism is strongly associated with the development of unipolar depressive disorder, bipolar disorder and schizophrenia [R, R1].
•         C677T mutation is associated with the risk of development of autism spectrum disorders [R, R1, R2, R3].
•         It has been shown that MTHFR mutations are linked with the development of Alzheimers and Parkinsons disorders [R, R1].
•         The MTHFR polymorphisms may be linked to multiple sclerosis but the evidence in controversial [R, R1, R2].
•         MTHFR polymorphisms confer susceptibility to migraines with or without aura [R, R1, R2].
•         The C677T polymorphism may contribute to an elevated increase of the risk for diabetes or diabetic nephropathy in patients with type II diabetes. The risks vary between Caucasian, Asian, Arabic and Chinese Han populations [R, R1, R2, R3].
•         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. A series of studies that have been conducted within the last 20 years have demonstrated a link between MTHFR and several forms of cancer such as ovarian, oesophageal, stomach, prostate and bladder cancer. However, the ethnicity and folate consumption were found to have a big impact on the development of cancer and interfere with the outcome of the studies. For an extensive list of the studies that investigated the link between different types of cancer and MTHFR see [R, R1].

Supplement with if you have lower MTHFR function: 1-2 caps Methyl Guard Plus

Supplementation of methylcobalamin (vitamin B12) and methylfolate, which reduces homocysteine level [R].

Also, Vitamin B6 and phosphatidylserine can be used to divert homocysteine to cystathione, preventing high levels of homocysteine. You might 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, red meat, and bread will 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. The minimum daily requirement of folate is 50 ¼g, although the current recommended intake is 400 ¼g/ day for the average adult. During pregnancy folate supplementation needs to be increased to 600 ¼g/ day [R]. However, folate supplementation is known to mask anemia caused by insufficient levels of vitamin B12. Therefore, you should consult your doctor before supplementing with it [R].

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.