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SHMT1 and One Carbon Metabolism: What Your Genotype Means

The SHMT1 gene encodes serine hydroxymethyltransferase 1, an enzyme that plays a central role in folate dependent one carbon metabolism. SHMT1 converts serine and tetrahydrofolate into glycine and 5,10-methylenetetrahydrofolate. These products support DNA synthesis, nucleotide balance, and the supply of methyl groups for the Methionine Cycle and methylation reactions. Proper SHMT1 function helps maintain healthy gene regulation, detoxification, and homocysteine balance. Variations in SHMT1 can subtly shift how folate is used by the body and influence nutritional needs under stress, high DNA synthesis demand, or low dietary folate.

Why SHMT1 Genotype Matters

  • SHMT1 directs folate toward either DNA synthesis or methylation. Small changes in enzyme function can change availability of folate intermediates.
  • Impaired folate flow can influence thymidylate synthesis, methylation capacity, and homocysteine clearance.
  • Genetic differences often interact with diet and lifestyle. Genotype is one factor among many that determine individual nutrient needs.

Genetic Interpretations

2 effect alleles (AA) — what this can mean

The AA genotype at rs1979277 results in an amino acid substitution in SHMT1. Literature reports are mixed. Reduced SHMT1 activity has more often been tied to the CC genotype in some studies, and AA has not been consistently associated with reduced enzyme function. Some evidence links AA with altered thymidylate synthase activity, which can change DNA synthesis demands.

Practical implications: AA is not typically linked to clear impairment in folate metabolism, but maintaining good folate status and supporting cofactors helps ensure robust methylation and nucleotide balance, especially during times of increased demand.

1 effect allele (AG) — what this can mean

The AG genotype indicates one copy of the effect allele. In most people this results in near normal SHMT1 enzyme activity. The heterozygous state may allow subtle shifts in levels of folate intermediates under conditions of low dietary folate, high cell division, or increased methylation demand.

Practical implications: With one effect allele, most people will do well with a balanced intake of folate and methylation cofactors. Pay attention to diet and nutrient status if you have additional genetic variants or health conditions that affect one carbon metabolism.

0 effect alleles (GG) — what this can mean

The GG genotype is associated with typical SHMT1 enzyme function. With normal activity, the Folate Cycle and Methionine Cycle are more likely to be well supported, provided dietary intake of folate and B vitamins is sufficient.

Practical implications: Standard dietary recommendations for folate and B vitamins usually support healthy methylation and nucleotide synthesis in people with this genotype.

Diet Recommendations

  • Prioritize natural food sources of folate: dark leafy greens, asparagus, Brussels sprouts, lentils, chickpeas, and avocado.
  • Balance dietary B vitamins: include foods rich in B2 (riboflavin), B6 (pyridoxine), and B12 (cobalamin). Good sources are eggs, lean meats, poultry, dairy, fortified whole grains, nuts, and seeds.
  • Include choline sources to support methyl donation: eggs, organ meats, soybeans, and cruciferous vegetables contain choline or its precursors.
  • Maintain steady protein intake for serine and glycine precursors. Beans, legumes, lean animal protein, and dairy contribute to amino acid pools used by SHMT1.
  • Limit excessive alcohol and highly processed foods that can reduce B vitamin absorption and increase folate needs.

Supplement Considerations

Supplements can help when dietary intake is insufficient or increased needs exist. Consult your healthcare provider before starting any supplement.

  • Folate: If supplementing, consider methylfolate (5-MTHF) or folinic acid if recommended by your provider. Standard folic acid is widely used, but some individuals prefer bioactive folate forms.
  • Vitamin B12: Methylcobalamin or cyanocobalamin as directed. B12 supports the Methionine Cycle and helps keep homocysteine in check.
  • Vitamin B6 and B2: Pyridoxine and riboflavin support steps in one carbon metabolism and related enzymes.
  • Choline: Supplementation may help methylation support in people with low dietary intake.
  • Multivitamin: A balanced B vitamin complex with folate and B12 can provide broad support when diet is inconsistent.

Lifestyle and Practical Steps

  • Maintain a balanced, nutrient-rich diet. Small consistent food choices matter more than sporadic supplementation.
  • Aim for regular meal timing. Consistent intake of micronutrients supports steady one carbon metabolism.
  • Manage stress and get regular sleep. Stress and poor sleep can increase inflammatory and methylation demands.
  • Limit alcohol intake and smoking. Both increase nutrient needs and can impair folate status.
  • During pregnancy planning or pregnancy, ensure adequate folate intake according to provider guidance.

Lab Tests and Monitoring

  • Homocysteine: Elevated homocysteine can indicate functional insufficiencies in folate, B12, or B6 and helps assess methylation support.
  • Serum folate and red blood cell folate: These tests give short term and longer term folate status, respectively.
  • Vitamin B12 and methylmalonic acid (MMA): Useful to confirm B12 status.
  • Other nutrient panels: B2, B6, choline status, and comprehensive metabolic panels can be helpful if symptoms or risk factors exist.

When to Talk with Your Healthcare Provider

  • If you have symptoms like unexplained fatigue, neuropathy, cognitive changes, or a history of elevated homocysteine.
  • If you are pregnant or planning pregnancy and want personalized folate and B vitamin guidance.
  • If you have other genetic variants affecting one carbon metabolism or a medical condition that influences nutrient absorption.
  • Before starting supplements, especially if you take medications or have chronic health conditions.

PlexusDx does not provide medical advice. This information is educational and describes genetic predispositions and general lifestyle, diet, and supplement options that may support one carbon metabolism. Always consult your healthcare provider for medical advice, diagnosis, or treatment tailored to your health history and current condition.