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Vitamin B12 and Methylation: What Your Genetics Can Tell You

Vitamin B12 (cobalamin) is a critical nutrient that supports the methionine synthase enzyme, which remethylates homocysteine into methionine using 5-methyltetrahydrofolate from the folate cycle. This reaction replenishes S-adenosylmethionine (SAMe), the universal methyl donor needed for DNA methylation, neurotransmitter production, lipid metabolism, and many detoxification reactions. When B12 is low, or when folate-related enzymes are less active, the body may shift toward the betaine (BHMT) pathway to maintain methionine and SAMe. That backup can help but does not fully replace the folate–B12 pathway, so maintaining adequate B12 is central to methylation balance and related aspects of health, including energy, mood, cognition, and detox capacity.

How to interpret this genetic result

This report looks at the rs9606756 variant linked to vitamin B12 status. Variations at this location are associated with differences in B12 availability, which can influence methionine synthase efficiency and overall methylation capacity. Below are clear, genotype-specific interpretations and practical steps you can take.

2 effect alleles — GG (higher risk for lower B12)

What this means: Carrying two copies of the effect allele (GG) is associated with lower vitamin B12 levels, which may come from differences in absorption, transport, or circulating B12. Reduced B12 can limit methionine synthase activity, raise homocysteine, and increase reliance on the betaine/BHMT backup pathway. Over time this can stress methylation-dependent systems.

Practical steps:

  • Test: Order a blood B12 and, if available, methylmalonic acid (MMA) and homocysteine to assess functional B12 status.
  • Diet: Prioritize B12-rich foods — beef, liver, fish (salmon, trout), shellfish, eggs, dairy, and fortified foods. If you limit animal products, focus on fortified plant foods.
  • Supplement: If tests show low or borderline B12, consider a daily methylcobalamin supplement in the range of 250 to 1,000 mcg. Higher therapeutic doses can be used under clinician guidance if MMA or homocysteine remain elevated.
  • Support nutrients: Ensure adequate folate (preferably 5-MTHF if recommended by your clinician) and choline to support alternate methylation routes and overall methyl balance.
  • Follow-up: Recheck B12 and MMA 8 to 12 weeks after starting supplementation or dietary changes, and monitor homocysteine if elevated.
1 effect allele — AG (slight tendency to lower B12)

What this means: Carrying one effect allele (AG) may modestly lower B12 status compared with the non-effect genotype. This could slightly reduce methionine synthase efficiency and raise reliance on backup pathways, but effects are usually mild and modifiable by diet and lifestyle.

Practical steps:

  • Test: Check blood B12 and consider measuring homocysteine or MMA if you have symptoms like fatigue, cognitive changes, or follow a plant-based diet.
  • Diet: Include regular servings of fish, shellfish, poultry, eggs, dairy, or fortified foods.
  • Supplement: If your diet is low in animal foods or tests show borderline levels, consider a routine low-to-moderate B12 supplement such as methylcobalamin or cyanocobalamin (commonly 250 mcg daily).
  • Lifestyle: Limit excessive alcohol which can impair B12 absorption, and be aware that medications like proton pump inhibitors and metformin can reduce B12 over time; discuss with your clinician.
  • Monitoring: If you adopt supplementation, repeat testing as advised by your clinician to confirm improvement.
0 effect alleles — AA (typical B12 status expected)

What this means: Carrying two non-effect alleles (AA) is associated with typical B12 levels for this genetic marker. Methionine synthase function and the folate–B12 remethylation route are expected to operate normally for this variant.

Practical steps:

  • Diet: Continue a balanced intake of B12-containing foods such as eggs, dairy, fish, poultry, and fortified products.
  • Risk groups: If you are over 60, follow a vegetarian or vegan diet, or take medications known to affect B12 absorption, consider periodic B12 checks and discuss supplementation with your clinician.
  • Prevention: Maintain adequate folate and choline intake through diet to support methylation and overall one-carbon metabolism.
  • Testing: Routine testing is not required unless symptoms or risk factors are present, but periodic checks can be helpful in certain life stages or health conditions.

Dietary and supplement recommendations

  • Food sources: Prioritize animal-sourced foods for natural B12 — clams, beef liver, sardines, salmon, eggs, yogurt, and fortified cereals or plant milk if you avoid animal products.
  • Supplements: Methylcobalamin is commonly recommended for better tissue uptake, with typical maintenance doses from 250 to 1,000 mcg daily. Cyanocobalamin is an effective and economical alternative. Use higher or injectable doses only under clinician supervision if deficiency is confirmed.
  • Support nutrients: Adequate folate (consider 5-MTHF if testing or clinical history suggests issues) and choline are helpful for methylation balance. A B-complex vitamin that includes B6, B2, and folate can support one-carbon metabolism.

Lifestyle and medication considerations

  • Medications: Proton pump inhibitors and metformin can impair B12 absorption over time. If you take these medications, discuss monitoring with your clinician.
  • Alcohol: Limit heavy alcohol use because it can affect absorption and liver storage of B12.
  • Aging: Individuals over 60 commonly have reduced stomach acid and intrinsic factor changes that impair B12 absorption; routine testing and supplementation are often recommended.
  • Vegetarian and vegan diets: Those avoiding animal products should rely on fortified foods and consider regular supplements to prevent deficiency.

Recommended lab tests

  • Serum vitamin B12 — general screening for B12 status
  • Methylmalonic acid (MMA) — a sensitive marker of functional B12 deficiency
  • Plasma homocysteine — elevated levels can indicate disrupted methylation
  • Consider folate and RBC folate if methylation concerns exist

PlexusDx provides educational information on genetic predispositions only. This content is not medical advice. Always consult your healthcare provider before starting any new supplement, changing medications, or making significant dietary or lifestyle changes. Your clinician can interpret genetic and lab results in the context of your medical history, symptoms, and current medications to create a personalized plan.