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Understanding DHFR and What Your rs1650697 Genotype Means

The DHFR gene makes the enzyme dihydrofolate reductase, a key player in the Folate Cycle. DHFR converts dihydrofolate into tetrahydrofolate, the active folate form that carries methyl groups used to build DNA and RNA. Adequate DHFR activity supports production of purines and thymidine, cell growth, replication, and repair. When DHFR activity is reduced, the body may struggle to produce usable folate, which can impair methylation, increase homocysteine, and affect overall metabolic and cellular health.

Why this matters for health

  • Lower DHFR function can limit conversion of synthetic folic acid into bioactive folate.
  • Reduced availability of 5-methyltetrahydrofolate, or 5-MTHF, can impair remethylation of homocysteine to methionine.
  • Over time, these shifts can contribute to elevated homocysteine, altered methylation, and higher risk for folate-sensitive conditions such as cardiovascular disease and neural tube defects.
  • Your rs1650697 genotype gives a clue about DHFR expression and how efficiently your body may activate folic acid.

Genetic Interpretation

2 effect alleles — AA

If you have the AA genotype for rs1650697, you carry two copies of the effect allele. This variant sits in the DHFR promoter and has been associated with decreased DHFR expression and lower enzyme levels. Decreased DHFR activity can reduce the ability to convert synthetic folic acid into tetrahydrofolate. That may cause a relative shortage of usable folate, impair production of 5-MTHF, and hinder remethylation of homocysteine to methionine. Over time this can raise homocysteine, reduce methylation capacity, and increase risk for folate-sensitive conditions including cardiovascular disease and neural tube defects.

Consider focusing on natural food folates and using pre-methylated folate (5-MTHF) supplements rather than folic acid to bypass the DHFR step.

1 effect allele — AG

If you have the AG genotype for rs1650697, you carry one copy of the effect allele. The A allele is linked to reduced DHFR expression, so enzyme activity may be moderately decreased. The effect is usually less pronounced than in AA carriers, but partial inefficiency in converting folic acid into tetrahydrofolate is possible. This may be more noticeable if dietary folate intake is low or if folic acid is the primary source of folate.

Ensuring adequate intake of natural food folates and, when supplementing, choosing active folate (5-MTHF) rather than folic acid can help optimize methylation and reduce strain on the Folate Cycle.

0 effect alleles — GG

If you have the GG genotype for rs1650697, you do not carry the effect allele. This typical genotype is associated with normal DHFR expression. With sufficient DHFR activity, conversion of folic acid and dihydrofolate into tetrahydrofolate should proceed efficiently, supporting a healthy Folate Cycle. People with this genotype generally process dietary folates and folic acid supplements without impairment and are not at increased genetic risk at this position for reduced folate activation or methylation capacity.

Practical Nutrition and Supplement Recommendations

These recommendations focus on supporting folate status and methylation. They are educational and not medical advice.

  • Prefer whole food folates: Include leafy greens, legumes, asparagus, beets, citrus, avocado, and Brussels sprouts. Food folate comes in bioactive forms and supports overall nutrient balance.
  • Choose active folate supplements if needed: Consider 5-MTHF supplements instead of folic acid to bypass DHFR if you have reduced DHFR activity (AA or AG genotypes).
  • Balanced B vitamin support: B12 (methylcobalamin), B6 (pyridoxal-5-phosphate), and riboflavin (B2) support methylation and homocysteine metabolism. Look for forms that are bioactive when possible.
  • Avoid excessive folic acid: High doses of unmetabolized folic acid may accumulate when DHFR activity is low. If supplementing with folate, prefer 5-MTHF or food-based options.
  • Provide cofactors: Magnesium and zinc are important cofactors for enzymes in methylation and folate-related pathways. Ensure adequate dietary intake.

Lifestyle Recommendations

  • Eat a varied, nutrient-dense diet rich in vegetables, legumes, and lean protein to support folate and B vitamin status.
  • Limit alcohol intake because it can interfere with folate absorption and increase folate requirements.
  • Manage stress and sleep: Chronic stress and poor sleep can alter methylation and metabolic health, so prioritize restorative sleep and stress reduction practices.
  • Maintain regular physical activity: Exercise supports cardiovascular health and can help normalize homocysteine levels when combined with good nutrition.
  • Discuss prenatal planning with your healthcare provider: Folate needs are higher in pregnancy and preconception. If you are pregnant or planning pregnancy, speak with your provider about the best folate form and dose for you.

Blood Tests and Monitoring

  • Serum folate: Measures recent folate intake but can vary with diet.
  • Red blood cell folate: Better reflects longer term folate status and tissue stores.
  • Serum B12 and methylmalonic acid: Assess B12 status, which is essential for methylation.
  • Homocysteine: Elevated homocysteine can be a functional signal of impaired methylation or folate/B12 deficiency.
  • Routine labs: Work with your healthcare provider to interpret results in the context of your genotype, diet, supplements, and health history.

When to Talk to Your Healthcare Provider

  • If you are pregnant or planning pregnancy, to determine the appropriate folate form and dose.
  • If you have elevated homocysteine, symptoms of B vitamin deficiency, or chronic health conditions that may be influenced by folate status.
  • If you are taking medications that affect folate metabolism or if you are considering high dose supplements.

Important Disclaimer

PlexusDx does not provide medical advice. This information is educational and intended to help you understand how the DHFR rs1650697 genotype may influence folate metabolism and related health considerations. Always consult your healthcare provider before making changes to your diet, supplements, or medical care based on genetic information.