HSA | FSA CARDS ARE NOW ACCEPTED

How TMPRSS6 and Iron Status Influence Methylation, Antioxidant Defense, and Neurotransmitters

Iron plays a central role in several biochemical pathways that affect energy, mood, antioxidant defense, and methylation balance. Understanding how a common genetic variant in the TMPRSS6 gene can affect iron regulation helps explain why some people are more likely to have low iron and how that can ripple through important systems like glutathione production and neurotransmitter breakdown.

Why iron matters for methylation and antioxidant systems

  • Iron is a cofactor for enzymes that form heme, which is part of the CBS enzyme in the transsulfuration pathway. CBS helps divert homocysteine toward cysteine and ultimately glutathione, a major cellular antioxidant.
  • When iron is adequate, CBS activity supports antioxidant production and helps balance whether homocysteine is remethylated or sent toward glutathione synthesis.
  • Iron is also required for monoamine oxidases, enzymes that break down dopamine, norepinephrine, and serotonin. These processes intersect with methylation because neurotransmitter turnover influences methyl donor demand and overall biochemical balance.
  • Low iron can reduce CBS and monoamine oxidase activity. That can lead to higher oxidative stress, altered neurotransmitter levels, and extra strain on the methylation cycle.

What TMPRSS6 does

TMPRSS6 helps the liver regulate hepcidin, the hormone that tells the gut how much iron to absorb and signals tissues how much iron to release from stores. Variants in TMPRSS6 can change how efficiently your body senses iron and sets hepcidin, which affects your blood iron levels and ferritin over time.

Genetic interpretations

2 effect alleles (GG) — higher chance of lower iron status

If you have the GG genotype for rs4820268, you carry two copies of the effect allele. This version of TMPRSS6 is linked with altered regulation of hepcidin and a higher likelihood of lower blood iron and iron deficiency over time.

  • Possible effects: increased risk of low ferritin, fatigue, reduced exercise tolerance, and greater strain on methylation and antioxidant systems (lower glutathione production, altered neurotransmitter breakdown).
  • Actionable steps:
    • Get iron status testing: ferritin and complete blood count (hemoglobin/hematocrit). Discuss results with your clinician before starting supplements.
    • Diet: increase heme iron sources—lean red meat, poultry, fish—and include vitamin C at meals (citrus, bell peppers, strawberries) to boost absorption.
    • Timing: avoid taking iron with calcium-rich meals or with coffee or tea, which reduce absorption.
    • Supplements: consider iron supplementation only if blood tests confirm deficiency and under clinician guidance. Correcting iron can help restore CBS and monoamine oxidase activity and ease stress on methylation pathways.
1 effect allele (AG) — modest increased risk of lower iron

If you have the AG genotype for rs4820268, you carry one copy of the effect allele. This can modestly reduce TMPRSS6 efficiency at sensing iron and regulating hepcidin, making mildly lower iron status more likely over time.

  • Possible effects: subtle increases in fatigue or lower exercise tolerance if iron drops; small shifts in how much homocysteine is routed toward glutathione vs remethylation; potential changes in neurotransmitter turnover if iron becomes limiting.
  • Actionable steps:
    • Get baseline iron markers: ferritin and hemoglobin.
    • Diet: emphasize heme iron foods—lean red meat, poultry, seafood—and pair them with vitamin C sources to enhance absorption. Plant iron sources (beans, lentils, fortified grains) are useful when paired with vitamin C.
    • Supplements: only when lab tests indicate low iron, and use under medical supervision.
0 effect alleles (AA) — typical TMPRSS6 function

If you have the AA genotype for rs4820268, you have two copies of the non effect allele and are likely to have typical TMPRSS6 function. This generally supports balanced hepcidin regulation and standard iron absorption under usual conditions.

  • Possible effects: lower genetically driven risk of iron deficiency from TMPRSS6 alone; normal support for CBS and monoamine oxidase function assuming other factors are stable.
  • Actionable steps:
    • Maintain a balanced diet with mixed iron sources: heme iron from lean meats and non-heme iron from plant foods paired with vitamin C.
    • Occasional monitoring: check ferritin and hemoglobin with your clinician if life changes occur (pregnancy, heavy menstrual bleeding, GI symptoms, endurance training) or before starting iron supplements.

Practical diet and lifestyle tips to support iron, methylation, and antioxidant balance

  • Eat a variety of iron sources: Include lean red meat, poultry, fish, beans, lentils, tofu, and iron-fortified grains. Heme iron from animal sources is absorbed more efficiently.
  • Boost absorption with vitamin C: Add citrus fruits, bell peppers, kiwi, or tomatoes to iron-containing meals.
  • Limit inhibitors around meals: Avoid coffee or tea and separate high-calcium foods or supplements from iron-rich meals when you are trying to improve absorption.
  • Support glutathione: Ensure adequate protein intake for cysteine supply and consider foods rich in sulfur amino acids (eggs, poultry, cruciferous vegetables).
  • Exercise and sleep: Regular moderate exercise and sufficient sleep support energy metabolism and recovery; extreme endurance exercise can increase iron losses and should prompt monitoring.
  • Manage blood loss: If you have heavy menstrual bleeding or GI symptoms, discuss evaluation with your clinician as these increase iron needs.

When to test and follow up

Check ferritin and hemoglobin when you first learn about a TMPRSS6 variant that could affect iron. Repeat testing if symptoms develop (fatigue, breathlessness with exertion, pale skin, restless legs) or after starting dietary changes or supplements. Work with your clinician to interpret results and to choose the right form and dose of iron if needed.

Important disclaimer

PlexusDx provides educational information about genetic predispositions. This content is not medical advice. Always consult your healthcare provider for diagnosis and treatment decisions, and before starting supplements, major dietary changes, or new therapies.