DNA Health > Methylation
Methylenetetrahydrofolate Reductase
MTHFR 677 C>T
MTHFR 1298 A>C
Allele Frequency in Population
The 1000 Genomes Project Database and the genome Aggregation Database (gnomAD) reports global frequencies of 25% and 31% respectively, for the 677 T allele (NIH). The MTHFR 1298 C allele has a frequency of 25%, according to the 1000 Genomes Project Database.
Gene and SNP Summary
Methylenetetrahydrofolate reductase, encoded by MTHFR, is a key enzyme in the folate dependant methylation pathway and is responsible for the irreversible methylation of 5,10-methylene tetrahydrofolate (5,10-methylene THF) to 5-methyl tetrahydrofolate (5-Methyl THF). 5-Methyl THF is then used as an essential folate cofactor in the remethylation of homocysteine. The MTHFR 677T and 1298C alleles lead to a reduction in enzyme function, and have been associated with increased risk for raised homocysteine levels, especially in combination with inadequate B-vitamin status. Disorders associated with the SNPs include neural tube defects (NTDs), mood disorders and chronic diseases of lifestyle such as heart disease as well as certain cancers. A diet that is rich in methyl donors and adequate in vitamins B2, B6, B9 and B12 may negate the negative effects of these SNPs.
MTHFR
Function
MTHFR Gene Detail
The B vitamins, vitamin B2, B6 and B12, as well as B9 (Folate) are essential cofactors in the folate-mediated one-carbon metabolism and remethylation pathway; a process by which homocysteine is converted back into methionine. The MTHFR gene is located on chromosome 1p36.3 and encodes the riboflavin dependant enzyme, methylenetetrahydrofolate reductase, which is responsible for catalysing the irreversible, NADPH-dependent reduction of 5,10-methylene THF to 5-Methyl THF.
It should be noted that MTHFR activity is inhibited by S-adenosyl methionine (SAMe/AdoMet), due to feedback inhibition. The methylated 5-Methyl THF is then used as an essential folate cofactor by the enzyme, methionine synthase, for the remethylation of homocysteine back into methionine. This reaction also yields tetrahydrofolate (THF), which is then redirected back to MTHFR for methylation or towards DNA synthesis.
MTHFR
Variant
MTHFR 677 C>T
The common MTHFR 677 C>T SNP results in a more thermolabile enzyme with lower catalytic activity, where the CT genotype is associated with 70% enzymatic function and the TT genotype with 30% catalytic activity. This decrease in function leads to lower levels of 5-methyl THF, and increasing levels of 5,10-methylene THF and plasma homocysteine.
The T allele, specifically the TT genotype has been associated with increased levels of homocysteine, which is a risk factor for several health disorders and chronic diseases of lifestyle.
The SNP has also been linked with an abnormal S-adenosyl methionine: S-adenosyl homocysteine (SAM:SAH) ratio, which is an indicator of methylation status. These associations are especially marked when plasma levels of vitamin B 9 and B12 are low.
Vryer and Saffery reported that individuals with the TT genotype typically tend to have lower levels of DNA methylation compared to their CC counterparts.
MTHFR 1298 A>C
The MTHFR 1298 A>C SNP results in an amino acid change from glutamine to alanine. This functional change is associated with an altered activity of the enzyme and thus disruptions in the homocysteine remethylation pathway, leading to increased risk for raised homocysteine levels. It should be noted that MTHFR compound heterozygous variant genotype (MTHFR 677 CT & 1298 AC) individuals have a higher risk for hyperhomocysteinemia, and this deleterious effect is aggravated by folate deficiency. The MTHFR 1298 C allele, and specifically the CC genotype, has been linked to higher homocysteine levels and numerous chronic diseases, as well as fertility issues and risk for NTDs.
Yang et al. found that the C allele was associated with metabolic syndrome traits, especially with risk of hypertension. The SNP has also been strongly linked to CVD risk including ischaemic stroke. There is also an association between individuals with the AC and CC genotype and increased risk of certain cancers as well as psychiatric disorders. The risk phenotypes are particularly pronounced in individuals with low folate, riboflavin and vitamin B12 levels.
MTHFR
Interventions
In individuals who are genetically at risk of having higher homocysteine levels, due to MTHFR SNPs, it is recommended to ensure adequate folate, vitamin B2 and vitamin B12 intake. For those who have further increased requirements due to certain lifestyle factors or medication use, or who have poor dietary intake of the above nutrients, supplementation may be required. Examples of vitamin B-rich food sources can be viewed below.
MTHFR
Articles
The impact of MTHFR 677 C/T genotypes on folate status markers: a meta‑analysis of folic acid intervention studies
Colsen et al, 2017.
Association of the A1298C polymorphism in MTHFR gene with ischemic stroke
Kang et al, 2014.
Association of the A1298C polymorphism in MTHFR gene with ischemic stroke
Kang et al, 2014.
