Instalab ResearchMTHFR is an enzyme that helps convert 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, the primary form of folate circulating in the blood. This methylated form of folate is crucial because it donates a methyl group needed to convert homocysteine into methionine. That conversion requires vitamin B12 as a cofactor. Meanwhile, vitamin B6 participates in related pathways through transsulfuration, another mechanism the body uses to reduce excess homocysteine. Riboflavin (vitamin B2) is also directly involved because MTHFR requires it as a cofactor to function properly.
When the MTHFR gene carries mutations like C677T, the enzyme becomes less efficient. In people who inherit two copies of the T allele, enzyme activity can be reduced by up to 70% compared to individuals without the mutation. This reduced efficiency compromises the conversion of folate into its active methylated form, leading to higher homocysteine levels and fewer methyl donors available for DNA synthesis and repair. The result is a bottleneck in one of the body’s most important metabolic cycles.
Large population studies and clinical investigations consistently show that individuals with MTHFR mutations, particularly those who are homozygous for the C677T variant, have higher homocysteine levels and lower folate, vitamin B12, and vitamin B6 concentrations compared with those without the mutation.
Research in Malaysian populations demonstrated that folate and homocysteine metabolism were significantly impaired in individuals with the T allele, with the greatest disruption occurring in homozygous carriers. Similar findings emerged in Japanese adults, where high intake of folate and vitamin B12 was able to offset the homocysteine-raising effects of the mutation.
One of the clearest lessons from MTHFR research is that genes and nutrition interact closely. People with the TT genotype are far more sensitive to low dietary intake of folate, vitamin B12, vitamin B6, and riboflavin. A large Norwegian cohort study found that plasma homocysteine levels were dramatically higher in TT individuals, but this effect was substantially reduced when B vitamin status was adequate. The benefit was particularly striking for riboflavin, which lowered homocysteine levels most effectively in those with the mutation.
Intervention trials confirm these observations. In the SU.FOL.OM3 randomized controlled trial, people with the TT genotype experienced a smaller drop in homocysteine after five years of B vitamin supplementation compared with those without the mutation. Still, supplementation narrowed the gap significantly, showing that even though TT carriers may not respond as robustly, they gain clear benefits from ensuring strong B vitamin intake.
Taken together, these findings highlight an important truth: while we cannot change our genes, we can often change how they affect our health through nutrition. The MTHFR gene mutation test can be useful in patients who face unexplained high homocysteine levels, recurrent pregnancy loss, infertility, or early cardiovascular disease.
At the same time, carrying an MTHFR mutation is not a guarantee of health problems. Its impact depends on both the specific genetic variant and the individual’s nutritional environment. People with these mutations are more vulnerable when their intake of folate, vitamin B12, vitamin B6, and riboflavin is inadequate, but they can often balance the scales by maintaining strong nutritional status.
