rs1801133 — MTHFR C677T

MTHFR C677T — The Methylation Gatekeeper

MTHFR (methylenetetrahydrofolate reductase) is arguably the most talked-about gene in nutritional genomics, and for good reason. It encodes the enzyme that converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate ¹¹ The active form of folate that enters the methylation cycle (methylfolate), the biologically active form of folate that your body actually uses. Methylfolate is essential for the methylation cycle ²² The methylation cycle adds methyl groups to DNA, proteins, and neurotransmitters — essential for hundreds of reactions, which affects DNA repair, neurotransmitter production, detoxification, and hundreds of other biochemical reactions.

The Mechanism

The C677T variant (rs1801133) causes an alanine-to-valine substitution ³³ Alanine-to-valine substitution at position 222 of the enzyme (p.Ala222Val) at position 222 of the MTHFR enzyme. This makes the enzyme thermolabile ⁴⁴ Thermolabile: the enzyme loses stability and function at normal body temperature — it loses activity at body temperature. The AA genotype ⁵⁵ TT on the coding strand — 23andMe reports the complementary strand retains only about 30% of normal enzyme activity, while the AG genotype ⁶⁶ CT on the coding strand retains about 65%. This means less dietary folate and supplemental folic acid gets converted to the methylfolate your cells need.

The Evidence

The C677T variant is one of the most extensively studied genetic variants in human biology. A meta-analysis of over 80 studies⁷⁷ meta-analysis of over 80 studies
Wen YY et al. Meta-analysis across 82 studies confirming the MTHFR-homocysteine link confirmed that the TT genotype is associated with 25% higher homocysteine levels when folate intake is low. Elevated homocysteine is an independent risk factor for cardiovascular disease⁸⁸ cardiovascular disease
Mangoni AA & Jackson SHD. Homocysteine and cardiovascular disease. Am J Med, 2002, neural tube defects, and possibly cognitive decline. However, the key finding is that adequate folate intake essentially normalizes homocysteine in most TT individuals. A large meta-analysis⁹⁹ large meta-analysis
Clarke R et al. Homocysteine and coronary heart disease meta-analysis, 2012 found a 15% excess coronary heart disease risk in TT homozygotes compared to CC homozygotes.

The Folic Acid Question

Synthetic folic acid (found in fortified foods and cheap supplements) must be converted by MTHFR to become active methylfolate. If your MTHFR is working at only 30% capacity, this conversion is a bottleneck. Methylfolate supplements bypass this step entirely, which is why they are often recommended for people with the TT genotype. Riboflavin (vitamin B2) is an essential cofactor for MTHFR and has been shown to lower blood pressure¹⁰¹⁰ shown to lower blood pressure
McNulty H et al. showed riboflavin 1.6mg/day lowers blood pressure in MTHFR TT individuals by stabilizing the thermolabile enzyme in TT individuals by stabilizing the thermolabile enzyme.

Practical Implications

The MTHFR C677T variant is extremely common — about 10-15% of Europeans are TT and about 40% are CT. It is not a disease-causing mutation. With adequate folate (especially as methylfolate), B12, B2, and B6 intake, most people with the TT genotype function perfectly normally. The key is knowing your status so you can optimize your B vitamin strategy.

Interactions

The C677T variant interacts importantly with the A1298C variant (rs1801131) — compound heterozygosity (one copy of each) can reduce MTHFR activity to 40-50%. It also interacts with SLC19A1 (rs1051266), which controls folate transport into cells, and COMT (rs4680), which determines tolerance for methyl donors. Methotrexate, an antifolate drug, has increased toxicity in C677T carriers.