Summary of MTHFR
The MTHFR gene codes for an enzyme known as methylenetetrahydrofolate reductase or MTHFR. This enzyme is very important for the production of DNA and methylation pathways that are essential for all bodily functions [R]. 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].
It's better to have this gene increased most of the time.
The Function of MTHFR
Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine.
Recommended name:Methylenetetrahydrofolate reductase
- RS12121543 (MTHFR) ??
- RS1476413 (MTHFR) ??
- RS17037396 (MTHFR) ??
- RS17367504 (MTHFR) ??
- RS17375901 (MTHFR) ??
- RS1801131 (MTHFR) ??
- RS1801133 (MTHFR) ??
- RS2066462 (MTHFR) ??
- RS2066470 (MTHFR) ??
- RS2274976 (MTHFR) ??
- RS4846049 (MTHFR) ??
- RS4846051 (MTHFR) ??
- RS9651118 (MTHFR) ??
To see your genotype, you should be logged in and have a file with your genotype uploaded.
Top Gene-Substance Interactions
MTHFR Interacts with These Diseases
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.
Substances That Increase MTHFR
Substances That Decrease MTHFR
The MTHFR gene codes for an enzyme known as methylenetetrahydrofolate reductase or MTHFR. 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]. 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].
Conditions with Increased Gene Activity
|Condition||Change (log2fold)||Comparison||Species||Experimental variables||Experiment name|
Conditions with Decreased Gene Activity
|Condition||Change (log2fold)||Comparison||Species||Experimental variables||Experiment name|
The following transcription factors affect gene expression (R):
Allosterically regulated by S-adenosylmethionine.
- Flavin Adenine Dinucleotide Binding
- Methylenetetrahydrofolate Reductase (Nad(P)H) Activity
- Modified Amino Acid Binding
- Nadp Binding
- Protein Complex Binding
- Blood Circulation
- Cellular Amino Acid Metabolic Process
- Folic Acid Metabolic Process
- Heterochromatin Maintenance
- Homocysteine Metabolic Process
- Methionine Metabolic Process
- Regulation Of Histone Methylation
- Response To Amino Acid
- Response To Drug
- Response To Folic Acid
- Response To Hypoxia
- Response To Interleukin-1
- Response To Vitamin B2
- S-Adenosylmethionine Metabolic Process
- Tetrahydrofolate Interconversion
- Folic Acid
- Tetrahydrofolic Acid