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Gene, Diet, Disease

MTHFR and Folate Metabolism

About 85% of the general population carry at least one minor allele of the MTHFR gene. Green vegetables, folic acid fortified foods, and vitamin B supplements can help to reduce the risk for high blood homocysteine, a strong risk factor for cardiovascular diseases.

Folate, also known as vitamin B9, is a member of the water-soluble B family vitamins. The synthetic version is called folic acid. Folate primarily exists in green leaves while folic acid is mainly found in supplements and fortified foods.

Folate is needed to make the nucleotides dTTP, one of the four building blocks of DNA molecules. It is also essential for the metabolism of several amino acids (histidine, serine, glycine, cysteine and methionine). Amino acids are building blocks of proteins and precursors for many bioactive molecules. Folate is also required for the conversion of a “bad” amino acid, homocysteine, to an essential one, methionine.  This conversion reaction is responsible for the production of S-adenosylmethionine (SAM), which is the universal methyl donor for the cellular methylation (of DNA, RNA, protein, lipids and etc.) reactions. Therefore, folate is indispensible for normal cell growth and cell division (Fig.1).

Figure 1. Simplified folate metabolism pathways involved in methionine recycling, DNA synthesis, purine synthesis and methylation reactions (boxed red texts). The dietary components folate and methionine are colored in green. Key enzymes and vitamin B family cofactors are shaded light orange and dark green respectively. Homocysteine, the barometer of folate deficiency or folate metabolism dysfunction is shown in bold case. See the metabolism section for details.

Insufficient dietary folate intake, certain medical conditions and genetic variation that impairs folate metabolism may lead to hyperhomocysteinemia and disturbed DNA synthesis and/or DNA methylation reactions.  Hyperhomocysteinemia is a condition exists in about 5% of the general population and associates with increased risk for many disorders, including vascular and neurodegenerative diseases, auto immune disorders, birth defects, diabetes, renal disease, osteoporosis, neuropsychiatric disorders and cancer. Disturbed DNA synthesis causes DNA mutation and DNA repair deficiency while disturbed methylation alters gene expression patterns.  All lead to birth defects and various cancers.  Folate deficiency also causes anemia, a condition that occurs when there is insufficient hemoglobin in red blood cells to carry enough oxygen to cells and tissues. Tetrahydrofolate (THF), a metabolic intermediate of folate, is a cofactor of enzymes that are involved in the synthesis of heme, a functional component of hemoglobin.

MTHFR (methylenetetrahydrofolate reductase) is a key enzyme for folate metabolism (Fig.1). It catalyzes the irreversible conversion of one form of folate 5, 10-methylentetrahydrofolate (5, 10-MTHF) to another form 5-methyltetrahydrofolate (5-MTHF), the primary methyl donor for the remethylation of homocysteine to methionine. Two common MTHFR polymorphisms, 677C>T and 1298 A>C, are associated with decreased enzyme activities and increased risks for hyperhomocysteinemia, cardiovascular diseases and cancer. The distribution of these two, although varying significantly between and within ethnic groups, are quite high, with frequencies between 13-57% in all populations studied (Table 1).  Overall, about 85% of the general population carries at least one minor allele of them. In addition, functional interaction between these two polymorphisms results in an additive effect on MTHFR enzyme activity. The compound heterozygous genotype 677CT/1298AC (that is heterozygous at both sites), with a prevalence of approximately 14–23% in most ethnic groups (except Africans, Table 1), has the enzyme activity reduced to 48% of the wide type.  Among the 6 compound genotypes that accounts for 99.9% human population, the association with homocysteine accumulation (hence the risk for hyperhomocysteinemia) ranked from the strongest to the least in the following order: 677TT/1298AA > 677CT/1298AC > 677CT/1298AA = 677CC/1298CC > 677CC/1298AC > 677CC/1298AA (wild type).

Table 1. The percentage of MTHFR 677C>T and 1298A>C alleles and related genotypes in major ethnic groups. The genotypes that show the most effect on folate metabolism are color shaded.

Ethnicity 677C>T (Ala222Val) 1298A>C (Glu429Ala) Compound Heterozygote
Allele Genotype Allele Genotype
C T CC CT TT A C AA AC CC 677CT/1298AC
African 87 13 78 20 2 82 18 68 29 3 4
Asian 56 to 79 21 to 44 31 to 62 35 to 53 3 to 20 72 to 83 17 to 28 49 to 68 30 to 47 2 to 4 14 to 15
Caucasian 54 to 75 34 to 46 29 to 54 39 to 51 4 to 27 58 to 69 31 to 42 44 to 48 41 to 46 10 to 12 15 to 23
Hispanic 43 to 76 24 to 57 18 to 45 47 to 50 18 to 30 64 to 81 19 to 36 50 to 66 27 to 34 2 to 6 15

Since the reduced activity by MTHFR 677C>T and 1298A>C minor alleles can be compensated by increased folate intake, people who carry any one of them should follow strictly the DFE (Dietary Folate Equivalent) recommended by the Institute of Medicine of the National Academy of Sciences, USA (Table 2).

Table 2. DEF (Dietary Folate Equivalent) and UL (Upper Intake Levels) by the Institute of Medicine of the National Academy of Sciences (1998). The numbers represent amount of dietary folate (1 DEF= 1 μg folate).  For folic acid, since it is easier to be absorbed by human body, the amount should reduce accordingly (1 DEF = 0.6 μg folic acid).

Age (years)  DEF (μg/day) UL (μg/day)
1–3 150 300
4–8 200 400
9–13 300 600
14–18 (general population) 400 800
14–18 (pregnant women) 600 800
14–18 (lactating women) 500 800
19+ (general population) 400 1,000
19+ (pregnant women) 600 1,000
19+ (lactating women) 500 1,000



In addition to folate intake, the MTHFR minor allele carriers also need to make sure enough vitamin B2, B6 and B12 intake since all of these vitamins are cofactors for enzymes involved in different steps of folate metabolism (Fig.1).  In literature, dietary regimens that are designed to address folate metabolism are often called one carbon diet or methyl diet.  Nutrients in these diets include folate, choline, vitamin B2, B6, B12, and methionine.  These are primary methyl group donors in methylation reactions, including DNA and protein methylation. It is important to point out that the recommendation in Table 2 also has an upper intake level (UL) because long-term excess folate intake in the form of supplement (not in the natural food resource) can mask diseases in the nervous system caused by vitamin B12 deficiency. On the top of sufficient folate and vitamin B intake, methionine restriction is recommended for MTHFR 677TT, 1298CC or 677CT/1298AC genotype carriers.  Methionine increases homocysteine accumulation and exacerbates the adverse effects of reduced MTHFR activity.  Since dietary methionine is mostly found in animal proteins and folate is mainly found in vegetables, methionine restriction calls for vegetarian orientated diets. In vegetarian diet regimens, vitamin B12 supplement is strongly recommended since it is normally absent from fruit and vegetables. Furthermore, alcohol restriction is strongly advised for its interference with folate absorption.

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