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HNMT and Histamine: How Your Genetics Affect Histamine Clearance and Wellbeing

The HNMT gene encodes histamine N-methyltransferase, the enzyme that helps break down histamine inside cells by transferring a methyl group from S-adenosylmethionine (SAMe) to form N-methylhistamine. Because this reaction depends on methylation chemistry, HNMT links histamine regulation with the methionine/folate/B12 methylation pathway. When HNMT works well, intracellular histamine is cleared efficiently, helping keep immune responses, digestion, sleep, and mood in balance. When HNMT activity is reduced, especially in the setting of low SAMe or impaired methylation, intracellular histamine can accumulate and contribute to symptoms such as headaches, anxiety, sleep problems, flushing, or other histamine-related issues.

How to read this result

  • rs11558538 describes a common functional variant in HNMT.
  • Genotypes: TT = two effect alleles, CT = one effect allele, CC = zero effect alleles.
  • An effect allele is associated with reduced HNMT enzyme activity.
  • Genetics interacts with diet, nutrient status, and environment. Symptoms are more likely when methylation or SAMe production is compromised or when histamine exposure is high.

Summary of practical implications

  • If HNMT activity is reduced you may be more sensitive to intracellular histamine buildup, particularly in the brain and tissues where DAO is low.
  • Support for methylation and SAMe production—via folate, vitamin B12, and adequate protein/methionine—can help HNMT function.
  • Reducing dietary and environmental histamine load and optimizing gut health can lower overall histamine exposure.
  • Check important labs if symptoms are present to guide targeted interventions.

Genetic interpretation

TT — Two effect alleles (reduced HNMT activity)

The TT genotype is associated with reduced HNMT enzyme activity. This can impair intracellular histamine breakdown, especially in tissues where DAO is not active, and may increase the risk of histamine-related symptoms like headaches, sleep disturbance, anxiety, flushing, or brain fog. The effect is more likely to appear when methylation is not optimal (low folate, low B12, impaired methionine cycle, or low SAMe). Focus on supporting methylation and reducing histamine load.

  • Consider prioritizing dietary folate (leafy greens, legumes), vitamin B12 (animal foods or supplement if needed), and adequate protein for methionine.
  • Assess and support gut health to reduce histamine-producing bacteria and improve DAO where relevant.
  • Observe response to low-histamine diet trial and track symptom patterns.
CT — One effect allele (mildly reduced HNMT activity)

The CT genotype may cause a moderate reduction in HNMT activity. Many people with CT have no symptoms, but a modest decrease in intracellular histamine breakdown can become meaningful when methylation is suboptimal or histamine exposure is high. Lifestyle and nutrient strategies often prevent or reduce symptoms.

  • Support folate and B12 to keep SAMe available for methylation.
  • Monitor for intermittent histamine-related symptoms and consider dietary or environmental adjustments if patterns emerge.
CC — Zero effect alleles (typical HNMT activity)

The CC genotype is generally associated with normal HNMT function. Intracellular histamine clearance is expected to be effective when methylation is supported. Usual healthy nutrition and lifestyle measures typically maintain balance.

  • Continue regular intake of folate, B12, and adequate protein to support methylation.
  • Pay attention to overall histamine exposures and gut health as part of general wellbeing.

Practical recommendations

Diet

  • Follow a balanced, nutrient-dense diet rich in natural folate: leafy greens, asparagus, broccoli, beans, and lentils.
  • Ensure adequate vitamin B12 from animal sources or supplementation if you follow a vegan or vegetarian diet.
  • Include quality protein sources to provide methionine: fish, poultry, eggs, dairy, or plant proteins like soy and legumes.
  • Consider a trial of a low-histamine diet if you experience consistent histamine-related symptoms. Reduce aged, fermented, smoked, or long-stored foods; limit alcohol, cured meats, certain cheeses, and some fish preparations.
  • Eat foods that support gut diversity and barrier function, such as fiber-rich vegetables, prebiotic foods, and fermented foods if tolerated (note: some fermented foods are high in histamine and may need to be avoided during a low-histamine trial).

Supplements and nutrients to consider

  • Folate: Prefer methylated folate (5-MTHF) if you have methylation concerns or MTHFR variants, but speak with your clinician first.
  • Vitamin B12: Methylcobalamin or hydroxocobalamin are good options for methylation support if deficient.
  • SAMe: Can support methylation directly, but use under medical supervision because it can affect mood and interact with medications.
  • Magnesium: Supports many enzymatic reactions and can help with sleep and muscle relaxation.
  • Quercetin and vitamin C: Natural antihistamine and mast cell stabilizing effects for symptomatic relief; use short term and evaluate benefit.
  • Probiotics: Choose strains shown to support gut barrier and reduce histamine production; avoid histamine-producing strains during sensitive periods.

Lifestyle strategies

  • Prioritize sleep and regular sleep schedules to support methylation and brain histamine balance.
  • Manage stress with daily practices—breathing, mindfulness, moderate exercise—to reduce histamine release driven by stress.
  • Avoid or limit alcohol and common histamine-triggering exposures (smoke, strong fragrances) when symptomatic.
  • Record a symptom and food/environment diary to identify patterns that suggest histamine triggers.

Blood tests and clinical monitoring

  • Consider lab evaluation of serum vitamin B12, red blood cell folate, and homocysteine to assess methylation support.
  • Measure methylation-related markers and inflammatory markers if symptoms suggest systemic involvement.
  • Consult your healthcare provider about testing diamine oxidase (DAO) or histamine if there is clear clinical suspicion of histamine intolerance.

When to contact your healthcare provider

If you have persistent or severe symptoms such as frequent headaches, severe mood changes, sleep disruption, gastrointestinal distress, or allergic-type reactions, consult your healthcare provider. Use these genetic insights as educational context to discuss targeted testing and safe interventions with your clinician.

Important disclaimer

PlexusDx provides educational information about genetic predispositions only and does not provide medical advice. This report is not a diagnosis. Always consult your healthcare provider before starting or stopping any treatment, supplement, or major lifestyle change. Your provider can interpret these results in the context of your overall health, medications, and diagnostic testing.