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Choline, Folate and MTHFD1: How These Genes and Nutrients Work Together

Choline is an essential nutrient that supports methylation by feeding the betaine pathway. In the liver and kidney, choline is converted to betaine, which donates a methyl group to remethylate homocysteine through the betaine-homocysteine methyltransferase pathway. This route works independently of folate and vitamin B12 and serves as an important backup to preserve methionine and S-adenosylmethionine or SAMe. By helping keep homocysteine low and maintaining SAMe availability, the choline to betaine pathway supports DNA methylation, neurotransmitter production, and lipid metabolism. It adapts to changes in homocysteine and methionine load and can spare folate and B12 when those nutrients are limited.

The MTHFD1 gene encodes a multifunctional enzyme in the folate cycle that creates and moves one-carbon units needed for DNA synthesis, SAMe production, and repair. A common variant in MTHFD1, rs2236225, affects enzyme efficiency and therefore how much the body relies on folate versus choline-derived methylation. The sections below explain how each genotype affects methylation balance and practical approaches for diet, supplements, lifestyle, and monitoring.

Quick overview of practical goals

  • Support adequate folate status and active folate forms when indicated
  • Include choline-rich foods to supply the betaine backup pathway
  • Ensure supporting B-vitamins: B2 (riboflavin), B6, and B12
  • Monitor homocysteine when clinically appropriate and follow your healthcare provider's advice

Genetic interpretation for rs2236225 (MTHFD1)

Two effect alleles (AA) — higher reliance on choline/betaine

If your genotype is AA you carry two copies of the effect allele. This version of MTHFD1 is linked with lower enzyme efficiency, which means your cells may produce fewer usable folate-derived one-carbon units. As a result your body may rely more on the choline-to-betaine (BHMT) pathway to keep homocysteine and SAMe levels stable.

Potential implications

  • Increased chance of elevated homocysteine under stress, low folate or B12 intake, or during pregnancy
  • Greater need for folate-related nutrients to support DNA synthesis and methylation
  • Higher benefit from dietary choline to support the BHMT backup pathway

Diet recommendations

  • Prioritize choline-rich foods: eggs (yolks), liver, soy products, cruciferous vegetables, legumes, and quinoa
  • Eat folate-rich foods: dark leafy greens, asparagus, Brussels sprouts, beans, lentils, and fortified whole grains
  • Include complete protein sources to support B-vitamin status

Supplement and nutrient strategy

  • Discuss a targeted supplement with your clinician that may include methylfolate plus riboflavin (B2) and vitamin B12
  • Consider a choline supplement if dietary intake is low, especially during pregnancy or lactation after clinician approval
  • Ensure adequate B6 and general B-complex support when recommended

Lifestyle and monitoring

  • Have homocysteine tested if there is clinical concern, especially during pregnancy, when taking medications that affect folate, or with cardiovascular risk
  • Maintain a balanced diet, avoid excessive alcohol which can disrupt folate and choline metabolism, and manage stress
  • Work with a healthcare provider for personalized dosing and monitoring
One effect allele (AG) — moderate reduction in MTHFD1 efficiency

If your genotype is AG you carry one copy of the effect allele. This is associated with a moderate decrease in MTHFD1 activity. Your folate cycle may run a bit less efficiently, which can slightly limit the supply of folate-derived one-carbon units used for remethylating homocysteine and making SAMe.

Potential implications

  • Mild strain on the folate arm of methylation, which can increase need for folate and cofactors
  • Small benefit from additional choline intake as a complementary methyl source

Diet recommendations

  • Include leafy greens, legumes, liver (if acceptable), citrus, and fortified grains for consistent folate intake
  • Add choline-containing foods: eggs, soy, cruciferous vegetables, and nuts
  • Balance meals with protein and healthy fats to support nutrient absorption

Supplement and nutrient strategy

  • Consider ensuring adequate active folate and B12 through diet or clinician-guided supplements
  • Riboflavin (B2) can support folate metabolism and may be helpful in combination with folate

Lifestyle and monitoring

  • Routine attention to diet typically suffices; test homocysteine if symptoms or clinical risk factors appear
  • Avoid chronic alcohol overuse and manage conditions that impair nutrient absorption
No effect alleles (GG) — typical MTHFD1 function

If your genotype is GG you carry two copies of the non effect allele and MTHFD1 activity is expected to be normal. Folate and choline metabolism and the supply of one-carbon units should function efficiently, supporting balanced homocysteine remethylation and SAMe production.

Potential implications

  • Lower genetic risk for folate-related bottlenecks in methylation
  • Still dependent on adequate dietary intake of folate, choline, and B-vitamins

Diet recommendations

  • Maintain a varied diet with leafy greens, beans, eggs, soy, and liver as appropriate
  • Consider a multivitamin if dietary intake is limited or during times of increased need

Supplement and nutrient strategy

  • Supplementation is usually not necessary unless dietary intake or clinical context indicates it
  • Ensure B2, B6, and B12 are adequate for overall methylation support

Lifestyle and monitoring

  • Regular healthy eating, moderate alcohol use, and addressing malabsorption conditions will help preserve methylation balance

When to talk with your healthcare provider

  • If you are pregnant, planning pregnancy, breastfeeding, or experiencing rapid growth periods speak with your clinician about folate, choline, and B12 needs
  • If you have a history of elevated homocysteine, cardiovascular disease, cognitive changes, or symptoms suggesting nutrient deficiency ask about testing and personalized recommendations
  • Before starting any supplements, particularly methylfolate, high dose choline, or B12, consult your healthcare provider to ensure safety and correct dosing

Important disclaimer

This information is educational and relates to genetic predispositions only. PlexusDx does not provide medical advice. Always consult your healthcare provider before making changes to your diet, supplements, or medical care. Genetic results are one piece of your health picture and should be considered alongside clinical factors, personal health history, and professional guidance.