Disease	Score

Substances	Interaction	Organism	Category

Substances	Interaction	Organism	Category

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].

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].

Condition	Change (log2fold)	Comparison	Species	Experimental variables	Experiment name

Condition	Change (log2fold)	Comparison	Species	Experimental variables	Experiment name

The following transcription factors affect gene expression:

• PPAR-gamma1
• PPAR-gamma2
• p53
• XBP-1
• AML1a

Enzyme Regulation:

Allosterically regulated by S-adenosylmethionine.

Molecular Function:

• Flavin Adenine Dinucleotide Binding
• Methylenetetrahydrofolate Reductase (Nad(P)H) Activity
• Modified Amino Acid Binding
• Nadp Binding
• Protein Complex Binding

Biological Processes:

• 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 Folic Acid
• Response To Hypoxia
• Response To Interleukin-1
• Response To Vitamin B2
• S-Adenosylmethionine Metabolic Process
• Tetrahydrofolate Interconversion

Drug Bank:

• Cyanocobalamin
• L-Methionine
• Menadione
• Fluorouracil
• Folic Acid
• Riboflavin
• Tetrahydrofolic Acid
• Benazepril
• Methotrexate

*synonyms