The methylation cycle runs 24 hours a day in every cell. Governing gene expression, neurotransmitter synthesis, homocysteine clearance, and DNA repair.
The complete folate and one-carbon metabolism pathway, from MTHFR through the B12-dependent remethylation cycle to the transsulfuration escape route and B12 absorption efficiency.
The Biology
One-carbon metabolism. The network of reactions that moves methyl groups through the cell. Is the engine behind epigenetic regulation, amino acid processing, and the synthesis of key neurotransmitters including dopamine, serotonin, and norepinephrine. When this pathway functions suboptimally due to genetic variants in the rate-limiting enzyme MTHFR or its cofactor-regenerating partners, the downstream effects can include elevated homocysteine, impaired DNA methylation, and reduced glutathione production.
What Varia Analyzes
Seven variants covering the complete methylation cycle. MTHFR C677T (rs1801133) and A1298C (rs1801131), the two primary rate-limiting variants that popularized the field; MTR A2756G (rs1805087), governing B12-dependent homocysteine remethylation; MTRR A66G (rs1801394), which regenerates the MTR enzyme after oxidative inactivation; CBS (rs234706), governing the transsulfuration pathway that clears homocysteine to cystathionine; BHMT (rs3733890), the betaine-dependent backup remethylation pathway; and FUT2 secretor status (rs601338), which determines B12 absorption efficiency in the gut and Bifidobacterium colonization. An upstream variable that can impair the entire pathway regardless of MTHFR status.
Why It Matters
Compound heterozygosity. One C677T allele plus one A1298C allele. Produces functional impairment equivalent to C677T homozygosity and is present in approximately 15% of the population. The FUT2 non-secretor finding (approximately 20% of people of European descent) is particularly underappreciated: it reduces B12 absorption efficiency regardless of dietary intake, and when combined with MTHFR or MTR variants, creates a compounding B12 dependency that dietary supplementation alone may not address without attention to the form of B12 used.
Key sources
- Frosst P, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995.
- van der Put NM, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects. Am J Hum Genet. 1998.
- Blom HJ, Smulders Y. Overview of homocysteine and folate metabolism with special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis. 2011.
- Wilson A, et al. A common variant in methionine synthase reductase combined with low cobalamin increases risk for spina bifida. Mol Genet Metab. 1999.
- Rausch P, et al. Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 genotype. PNAS. 2011.