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Folate, MTHFR, and What Your Genes Mean for Methylation

Folate is a cornerstone nutrient for methylation, the biochemical system that supports DNA maintenance, neurotransmitter production, lipid metabolism, and detoxification. In the body folate is converted into its active form 5-methyltetrahydrofolate (5-MTHF). That active folate donates a one-carbon unit to convert homocysteine into methionine, replenishing S-adenosylmethionine (SAMe) — the universal methyl donor used throughout the body.

The MTHFR enzyme helps convert 5,10-methylene-THF into 5-MTHF. When MTHFR activity is reduced, the supply of active folate can be limited, which can slow remethylation and impact overall methylation capacity. Compared with synthetic folic acid, 5-MTHF is already active and bypasses certain enzymatic steps, so it can be especially helpful when MTHFR or DHFR activity is lower.

Why this matters for health

  • Low active folate or impaired remethylation may raise homocysteine, a marker associated with cardiovascular and other metabolic risks.
  • Reduced methylation capacity can affect energy, mood, neurotransmitter balance, and detoxification pathways.
  • During pregnancy, adequate active folate is essential for optimal fetal development and to reduce neural tube risk.

Tests and monitoring to consider

  • Plasma homocysteine — evaluates remethylation performance.
  • Serum folate and red blood cell folate — show short- and long-term folate status.
  • Vitamin B12 (serum and, if needed, methylmalonic acid) — B12 is required for remethylation.
  • Riboflavin (B2) status may be relevant because it is a cofactor for MTHFR activity.
  • Talk with your healthcare provider before ordering tests or starting supplements.

Practical diet, supplement, and lifestyle recommendations

These suggestions are intended to support methylation and general health. PlexusDx does not provide medical advice. Always consult your healthcare provider before starting new supplements, changing medications, or making major diet changes.

Diet

  • Eat folate-rich whole foods daily: dark leafy greens (spinach, kale), legumes (lentils, chickpeas, beans), beets, asparagus, and liver if you eat animal products.
  • Include B12 sources if you consume animal products: fish, meat, eggs, and dairy. If you follow a vegetarian or vegan diet, talk to your clinician about B12 supplementation.
  • Choose whole grains and fortified foods when appropriate to help maintain folate and B-vitamin intake.
  • Support gut health: a balanced microbiome helps nutrient absorption. Prioritize fiber, fermented foods, and adequate hydration.

Supplements to discuss with your clinician

  • Low-dose methylfolate (L-5-MTHF) when active folate support is needed. Dosage and necessity depend on genotype, labs, and clinical context.
  • Methylcobalamin (active B12) to pair with methylfolate and support remethylation.
  • Riboflavin (vitamin B2) to support MTHFR enzyme function.
  • A balanced B-complex may help ensure adequate cofactor status for methylation and related pathways.
  • Avoid high-dose folic acid supplements without clinical indication, especially if functional folate metabolism is a concern; discuss with your provider.

Lifestyle

  • Manage stress: chronic stress can increase nutrient demand and affect methylation. Use sleep hygiene, mindfulness, and regular physical activity.
  • Regular moderate exercise supports cardiovascular health and metabolic flexibility.
  • Avoid smoking and excess alcohol, both of which can disrupt methylation and nutrient status.
  • Maintain a healthy body weight and monitor cardiovascular risk factors as recommended by your provider.

Genetic interpretation for MTHFR rs1801133

Two effect alleles (AA) — reduced MTHFR activity

If you have the AA genotype for rs1801133, you carry two copies of the effect allele and typically have notably reduced MTHFR enzyme activity, often around a 70 to 80 percent reduction. That means your conversion of folate into the active 5-MTHF form can be much less efficient. When active folate is limited, homocysteine may rise and methylation capacity can be compromised.

Practical considerations

  • Diet: Prioritize folate-dense foods such as dark leafy greens, legumes, beets, and if tolerated, small amounts of liver.
  • Supplements: Discuss a low-dose methylfolate (5-MTHF) supplement with your clinician. Use alongside adequate vitamin B12 (methylcobalamin) and riboflavin (B2) to support the pathway.
  • Testing: Consider checking homocysteine, serum and red blood cell folate, and B12 before and after interventions.
  • Life stage: During pregnancy or when planning pregnancy, speak with your provider urgently about folate form and dose to support fetal development.
One effect allele (AG) — moderately reduced MTHFR activity

If you have the AG genotype for rs1801133, you carry one copy of the effect allele and typically have moderately reduced MTHFR function, often around a 40 percent decrease. Your body may produce active 5-MTHF more slowly and may rely more on supportive cofactors like riboflavin and B12.

Practical considerations

  • Diet: Keep folate intake steady with leafy greens, legumes, and fortified whole grains. A balanced intake usually supports normal function.
  • Supplements: If tests or symptoms suggest suboptimal folate or elevated homocysteine, discuss a low-dose methylfolate and riboflavin with your clinician. Methylcobalamin is recommended if B12 status is suboptimal.
  • Monitoring: Check homocysteine if you have cardiovascular risk factors or symptoms that might relate to methylation.
  • Stress and nutrition: Under periods of illness, high stress, or poor diet, your need for active folate and B vitamins may be higher.
No effect alleles (GG) — typical MTHFR function

If you have the GG genotype for rs1801133, you carry two copies of the non-effect allele and are likely to have typical MTHFR function. Your body usually converts dietary folate to active 5-MTHF effectively, supporting normal homocysteine regulation and methylation processes.

Practical considerations

  • Diet: Maintain a folate-rich diet with leafy greens, legumes, beets, and fortified grains.
  • Supplements: Routine B12 and B2 intake through diet or a standard B-complex can help if your diet is low in animal products.
  • Monitoring: Routine screening is usually not required unless symptoms or other health conditions suggest otherwise.

PlexusDx does not provide medical advice. The information here is educational about genetic predispositions and potential nutritional strategies only. Always consult your healthcare provider to interpret your genetic results in the context of your medical history, current medications, lab results, and life stage before starting supplements or treatment plans.