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MTHFD1 and One-Carbon Metabolism: What Your Genotype Means for Folate, Methylation, and Cellular Health

The MTHFD1 gene encodes a trifunctional cytoplasmic enzyme that plays a central role in the folate-dependent one-carbon pathway. By converting formate-derived carbon into 10-formyltetrahydrofolate (10-formyl-THF) and helping generate 5-methyltetrahydrofolate (5-MTHF), MTHFD1 links mitochondrial one-carbon output to purine synthesis and the production of S-adenosylmethionine (SAMe). SAMe is the body’s universal methyl donor and is essential for DNA methylation, neurotransmitter metabolism, and detoxification. Variants that reduce MTHFD1 efficiency can therefore affect nucleotide production, DNA repair, and methylation capacity.

Why this matters for health

  • Purine synthesis: 10-formyl-THF is required for making purine nucleotides needed for DNA and RNA production. Reduced MTHFD1 activity can slow cell replication and repair.
  • Methylation capacity: MTHFD1 helps maintain 5-MTHF levels that feed the methionine cycle and SAMe production. Lowered function can reduce methylation, which impacts gene regulation, neurotransmitter metabolism, and detox pathways.
  • Nutrient interactions: MTHFD1 function depends on adequate folate, riboflavin (B2), pyridoxine (B6), cobalamin (B12), choline, and methionine. Diet and micronutrient status can amplify or mitigate genetic effects.

What to monitor

  • Symptoms during increased demand: fatigue, poor recovery, or cognitive changes may reflect impaired one-carbon flux when demand is high or nutrient intake is low.
  • Laboratory markers: folate, RBC folate, serum B12, plasma homocysteine, and methylation-related markers (if available) can help assess functional one-carbon status.
  • Life stages with higher demand: pregnancy, rapid growth, chronic inflammation, and heavy physical training can increase one-carbon demand.

Genetic Interpretation

2 effect alleles (AA at rs2236225)

Carrying two copies of the effect allele is associated with reduced MTHFD1 activity. This genotype can limit efficient interconversion of one-carbon folates, including 10-formyl-THF for purine synthesis and the downstream 5-MTHF supply needed for methylation. When nutrient intake or cofactor availability is suboptimal, people with this genotype may experience reduced nucleotide production, slower cell turnover, and lower methylation capacity.

Practical considerations

  • Prefer folate as 5-MTHF rather than folic acid to directly support methylation pathways.
  • Ensure sufficient riboflavin (B2), B6, and B12 to support folate-dependent enzymes.
  • Support one-carbon inputs with choline and methionine rich foods to preserve SAMe production.
  • Monitor homocysteine and B-vitamin status periodically, especially during pregnancy or other high demand periods.
1 effect allele (AG at rs2236225)

One copy of the effect allele is associated with intermediate MTHFD1 efficiency. One-carbon flow is usually adequate but may be vulnerable under low folate intake or increased demand. Nutritional support tends to maintain methyl-donor availability and buffer episodes of increased need.

Practical considerations

  • Maintain a balanced intake of folate, and consider 5-MTHF if dietary folate is low or if taking multivitamins containing folic acid causes concerns.
  • Include foods high in B2, B6, and B12 and consider targeted supplementation if blood tests indicate deficiency.
  • Support choline intake through food or supplements when dietary intake is low, as choline can spare methyl groups.
0 effect alleles (GG at rs2236225)

Having two copies of the non-effect allele is associated with normal MTHFD1 function. Conversion among one-carbon folate forms typically supports purine synthesis and the methylation arm effectively. Standard dietary guidance to maintain folate and B-vitamin sufficiency is generally appropriate.

Practical considerations

  • Follow general recommendations for folate and B-vitamin intake, emphasizing whole food sources.
  • Monitor status only as part of routine care or if symptoms arise that suggest altered methylation or one-carbon metabolism.

Dietary Recommendations

  • Priority nutrients: consume foods rich in natural folate (leafy greens, legumes, asparagus), B12 (animal proteins, fortified plant foods if needed), B2 (dairy, eggs, lean meats), B6 (poultry, fish, potatoes), choline (eggs, soy, cruciferous vegetables), and methionine (eggs, meat, dairy, sesame seeds).
  • Choose 5-MTHF where possible in supplements or fortified products if you have reduced MTHFD1 activity or trouble tolerating folic acid.
  • Limit excessive alcohol intake because alcohol impairs folate absorption and one-carbon metabolism.
  • Include consistent protein at meals to supply methionine and support SAMe synthesis.

Supplement Recommendations

  • 5-MTHF: consider when functional folate support is needed or for those with reduced MTHFD1 activity.
  • Vitamin B12: supplement if levels are low or if you follow a vegetarian or vegan diet. Use methylcobalamin or hydroxocobalamin forms as preferred by your clinician.
  • Riboflavin (B2) and pyridoxine (B6): support enzymes in one-carbon metabolism; consider supplementation if dietary intake is inadequate.
  • Choline: consider supplemental phosphatidylcholine if dietary choline is low, especially during pregnancy.
  • Do not start high-dose supplements without consulting your healthcare provider. Tailor doses to lab results and life stage.

Lifestyle and Testing

  • Testing: consider measuring serum or RBC folate, serum B12, plasma homocysteine, and basic nutritional panels to guide personalized recommendations.
  • Pregnancy planning: optimize folate and B12 prior to conception and in early pregnancy to support nucleotide synthesis and methylation during fetal development.
  • Stress and sleep: chronic stress and poor sleep can increase metabolic demand. Prioritize sleep, stress management, and regular physical activity to support overall metabolic resilience.
  • Medication review: certain medications can affect folate or B12 status. Review medications with your healthcare provider to identify interactions.

How to Use This Information

This genetic information can help guide dietary choices, consideration of targeted supplements, and decisions about monitoring nutrient status. It is not a diagnosis and does not predict outcomes with certainty. Genetic predisposition interacts with diet, environment, medications, and lifestyle.

PlexusDx does not provide medical advice. This information is educational only. Always consult with your healthcare provider before making changes to medications, supplements, or major aspects of diet and lifestyle. Your clinician can interpret genetic results in the context of your full medical history, lab data, and personal goals.