| Perhaps the most studied SNP-containing gene of all, Methylene tetrahydrofolate reductase (MTHFR) allows conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, needed for conversion of homocysteine (HCy) to the protein-building amino acid methionine via methylation, in the rate-limiting step of the methyl cycle. MTHFR is a highly polymorphic gene, and genetic variation influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency. Lower MTHFR enzyme activity results in lower levels of methylated folate, leading to elevated homocysteine (HCy). Natural variation in this gene is common in healthy people. Although some variants have been reported to influence susceptibility to occlusive vascular disease, neural tube defects, Alzheimer's disease and other forms of dementia, colon cancer, and acute leukemia, findings from small early studies have not been consistently reproduced. Two of the most investigated are C677T (rs1801133) and A1298C (rs1801131) single nucleotide polymorphisms (SNPs). |
- Individuals with two copies of 677C (677CC) have the most common genotype. 677TT individuals (homozygous) have lower MTHFR activity than CC or CT (heterozygous) individuals.
- 1298AA is the "normal" homozygous, 1298AC the heterozygous, and 1298CC the homozygous for the "variant". The C mutation does not appear to affect the MTHFR protein. It does not result in thermolabile MTHFR and does not appear to affect homocysteine levels. It does, however, affect the conversion of MTHF to BH4 (tetrahydrobiopterin), an important cofactor in the production of neurotransmitters, production of nitric oxide, and detoxification of ammonia.