HSA | FSA CARDS ARE NOW ACCEPTED

Folate Cycle | CUBN | rs1801222 AA

The CUBN gene encodes cubilin, a protein essential for the absorption of vitamin B12 in the intestines, facilitating its transport into the bloodstream. Efficient B12 absorption is critical for maintaining healthy homocysteine levels and supporting the methylation cycle, where B12 acts as a cofactor in converting homocysteine into methionine. When CUBN function is compromised—whether due to genetic variation or environmental factors—it can lead to reduced B12 levels, elevated homocysteine, and disruptions in processes like DNA repair, neurotransmitter synthesis, and detoxification. Ensuring adequate intake of active B12 forms, such as methylcobalamin, can help support methylation and overall metabolic health.

Genotype Interpretation

You have the AA genotype for rs1801222, which means you carry two copies of the effect allele. This variant is located in the CUBN gene, which encodes cubilin—a receptor that plays a critical role in the intestinal absorption of vitamin B12 bound to intrinsic factor. The AA genotype is associated with reduced CUBN activity, affecting vitamin B12 absorption and increasing the risk of lower serum vitamin B12 levels.

Vitamin B12 is an essential cofactor for methionine synthase in the Folate Cycle, facilitating the remethylation of homocysteine to methionine—critical for producing S-adenosylmethionine (SAMe), the body’s universal methyl donor. Disruption of B12 availability can therefore influence methylation efficiency and downstream processes such as DNA synthesis, neurotransmitter balance, and detoxification.

Diet Recommendations

  • Emphasize B12-rich foods: Grass-fed red meat, liver, eggs, shellfish (clams, oysters, mussels), and dairy (if tolerated). However, with reduced cubilin activity, food sources alone may not normalize levels.
  • Include folate-rich foods: Dark leafy greens, legumes, asparagus, avocado—supports the Folate Cycle and helps balance homocysteine alongside B12.
  • Add choline-rich foods: Eggs, salmon, lecithin, quinoa, beets—supports the BHMT pathway, an alternate remethylation route that reduces strain on B12-dependent methionine synthase.
  • Limit alcohol and antacids: Both further reduce B12 absorption.
  • If COMT (rs4680 AA) or MAOA slow: Avoid high-dose methyl donors (like large amounts of methyl-B12 or methylfolate at once); balance with glycine and magnesium.

Supplement Recommendations

  • Vitamin B12: Prefer sublingual or liposomal forms to bypass absorption issues. Start with methylcobalamin (active) or adenosyl/hydroxo-B12 if sensitive to methyl groups. Dose range: 1000–5000 mcg daily (sublingual).
  • 5-MTHF (L-methylfolate): 400–800 mcg daily to support the folate cycle. Always pair with B12 to avoid the “methylfolate trap.”
  • Riboflavin (B2): 5–10 mg daily to support MTHFR enzyme activity.
  • Trimethylglycine (TMG): 250–500 mg daily to support the BHMT pathway (especially if homocysteine is high). Start low if COMT slow.
  • Creatine: 3–5 g daily to reduce demand on methylation for creatine synthesis.
  • Glycine: 3 g per meal (powder, collagen, or bone broth) to buffer methylation swings.

Genotype Adjustments

  • If MTRR variants present: Higher and more consistent B12 dosing may be required.
  • If MTHFR C677T AA: Prioritize methylfolate and riboflavin supplementation more strongly.

Lifestyle Recommendations

  • Support digestion: Optimize stomach acid with apple cider vinegar, bitters, or digestive enzymes since intrinsic factor and gastric acid are critical for B12 absorption.
  • Stress reduction: Meditation, yoga, and adequate sleep lower methylation demand (stress hormones require methyl groups for clearance).
  • Avoid smoking and excess alcohol: Both deplete folate, B12, and SAMe.
  • Balanced exercise: Moderate, regular exercise supports circulation and B12 transport.

PlexusDx Suggested Testing

Nutrition Deficiency Blood Test

  • Vitamin B12 (likely low with CUBN AA)
  • Folate
  • Homocysteine (functional marker of methylation imbalance)
  • Ferritin (low iron impairs methylation buffer system)

Methylation Panel

  • Homocysteine
  • Folate (B9)
  • Vitamin B12

Additional Considerations

  • Methylfolate trap risk: Without enough B12, folate gets “trapped” as 5-MTHF, worsening deficiency. Always supplement folate and B12 together.
  • Glutathione metabolism: Adequate glutathione is required for B12 intracellular utilization. Consider N-acetylcysteine (NAC) or precursors if oxidative stress is high.
  • Medication interactions: Antacids, PPIs, metformin, and oral contraceptives can worsen B12 absorption.