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How MTHFD1 Variants Affect Choline Needs and Health

Choline is an essential nutrient that supports brain function, liver health, muscle contraction, and energy metabolism. It is a building block for cell membranes and the neurotransmitter acetylcholine. The MTHFD1 gene makes an enzyme involved in processing folate. Folate and choline metabolisms are closely connected. Variations in MTHFD1 can reduce the efficiency of folate processing, which in turn increases the body’s reliance on choline to maintain key biochemical pathways, including methylation and DNA synthesis.

This article explains what the common MTHFD1 variant rs2236225 means for choline requirements and related health considerations. It also offers practical diet, supplement, lifestyle, and monitoring suggestions you can discuss with your healthcare provider.

Why folate and choline interact

Folate helps transfer one carbon units needed for building DNA and for generating methyl groups used in many processes. When folate processing is less efficient, the body shifts some of the burden to choline-derived pathways. That means if folate metabolism is impaired by an MTHFD1 variant, choline becomes more important to maintain normal methylation and prevent metabolic stress. Low choline intake under these circumstances can contribute to symptoms such as fatigue, muscle discomfort, and liver issues.

Dietary and lifestyle strategies

  • Foods high in choline: egg yolks, beef and chicken liver, salmon, cod, shrimp, lean poultry, and soybeans. Include these regularly if tolerated.
  • Foods high in folate: dark leafy greens (spinach, kale), broccoli, Brussels sprouts, lentils, chickpeas, black beans, asparagus, and fortified whole grain products.
  • Balance macronutrients: adequate protein supports methylation and liver function. Include healthy fats such as olive oil, nuts, and fatty fish to support choline absorption and brain health.
  • Limit alcohol: alcohol increases nutrient demands and can worsen liver stress. Reducing intake supports both folate and choline balance.
  • Regular physical activity: moderate exercise supports metabolic health, liver function, and energy levels.
  • Manage stress and sleep: chronic stress and poor sleep affect methylation and recovery. Prioritize sleep hygiene and stress management techniques.
  • Stay hydrated: adequate water intake supports metabolic reactions and overall wellness.

Supplements and tests to consider

  • Choline supplements: forms include choline bitartrate, citicoline (CDP-choline), and alpha-GPC. Discuss appropriate form and dose with your clinician based on diet and health history.
  • Folate: if dietary intake is low, consider folate supplementation under guidance. Note that folic acid and methylfolate are different forms; your provider can recommend the best option.
  • Other supportive nutrients: vitamin B12, B6, riboflavin, and betaine support methylation pathways. Check levels and supplement if needed after consulting your clinician.
  • Blood testing: consider tests such as serum folate, red blood cell folate, plasma choline, liver enzymes, and homocysteine to assess functional status and guide interventions.
AA genotype for rs2236225 (2 effect alleles)

You carry two copies of the effect allele. This genotype is associated with reduced MTHFD1 enzyme efficiency and an increased risk of inefficient folate processing. When folate processing is impaired, your body relies more on choline to support methylation, DNA synthesis, and other key biochemical pathways. Low choline intake in this context can increase the chance of symptoms related to folate and choline imbalance, such as fatigue, muscle aches, difficulty concentrating, or liver function disturbances.

Recommendations tailored to this genotype:

  • Prioritize regular intake of choline-rich foods: eggs, liver, fatty fish, soy, and legumes. Aim for dietary sources before relying solely on supplements.
  • Ensure daily folate from leafy greens, legumes, and fortified foods. If dietary folate is low, discuss supplementation with your provider.
  • Consider a choline supplement if blood tests show low levels or if dietary intake is inadequate. Work with your clinician to choose dose and form.
  • Monitor liver function and consider testing homocysteine, serum folate, and RBC folate periodically to evaluate metabolic status.
  • Support overall methylation with adequate B12, B6, and riboflavin intake as advised by your clinician.
AG genotype for rs2236225 (1 effect allele)

You carry one copy of the effect allele. This genotype is associated with moderately reduced MTHFD1 activity compared to the non-effect genotype. Your folate processing may be somewhat less efficient, which can increase reliance on choline for methylation and related pathways. While the impact is typically less pronounced than with two effect alleles, maintaining good choline and folate intake is still important.

Recommendations tailored to this genotype:

  • Include choline-rich foods several times per week: egg yolks, salmon, chicken, and soy products.
  • Maintain steady folate intake from leafy greens, beans, and whole grains. Consider a multivitamin with folate if dietary intake is inconsistent.
  • If you have symptoms such as unexplained fatigue or elevated homocysteine, discuss targeted testing with your provider.
  • Keep alcohol intake low and support sleep and stress management to reduce metabolic strain.
GG genotype for rs2236225 (0 effect alleles)

You carry no copies of the effect allele. This genotype is associated with efficient folate metabolism by the MTHFD1 enzyme. Your body is likely better able to process folate and therefore has less dependence on choline to compensate for folate-related functions. However, choline and folate are still essential nutrients for brain and liver health, so maintaining adequate intake remains important.

Recommendations tailored to this genotype:

  • Continue a balanced diet that includes choline and folate sources: eggs, fish, leafy greens, legumes, and whole grains.
  • Routine dietary intake is usually sufficient, but consider testing and supplementation if you have specific risk factors, pregnancy, liver disease, or symptoms suggestive of deficiency.
  • Support overall metabolic health with regular exercise, moderate alcohol intake, and good sleep.

When to consult your healthcare provider

  • If you are pregnant, planning pregnancy, or breastfeeding, discuss choline and folate needs with your provider. Both nutrients are important for fetal development.
  • If you have symptoms such as persistent fatigue, muscle pain, cognitive changes, or abnormal liver tests, seek medical evaluation and consider nutrient testing.
  • If you are taking medications that affect folate metabolism or liver function, review nutrient strategies with your clinician.
  • Before starting any new supplement, especially in the context of genetic results, confirm safety, dose, and interactions with your healthcare provider.

PlexusDx provides educational information about genetic predispositions and how they may influence nutrient needs and health. This content is not medical advice and is not a substitute for evaluation, diagnosis, or treatment by a qualified healthcare professional. Always consult with your healthcare provider before making changes to your diet, supplement routine, or medical care based on genetic information.