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Understanding Histamine and the HNMT Gene

Histamine is a powerful chemical messenger involved in immune responses, brain signaling, digestion, and regulation of blood flow. The body produces histamine during allergic reactions and other immune responses. To keep histamine levels balanced, the body uses enzymes that break it down. One important enzyme is produced by the HNMT gene. HNMT works by adding a methyl group to histamine, rendering it inactive. Variations in the HNMT gene can change how well this enzyme functions and may influence the risk of histamine-related symptoms including allergies, migraines, skin reactions, and some digestive complaints.

Why this matters for your health

If HNMT activity is reduced, histamine produced inside your body can accumulate and contribute to what is often called histamine intolerance. Symptoms can be wide ranging and include nasal congestion, sneezing, itching, hives, headaches or migraines, abdominal pain, bloating, diarrhea, and sometimes feelings of anxiety or flushing. Identifying a genetic tendency toward lower HNMT activity can help guide lifestyle, diet, and supplement strategies aimed at supporting histamine balance.

Genetic Interpretations

Two effect alleles (TT) — reduced HNMT activity

If your genotype is TT for rs11558538 you have two copies of the effect allele. This genotype is associated with reduced HNMT enzyme activity and higher odds of histamine intolerance. The HNMT enzyme methylates histamine to deactivate it. With two copies of this variant the enzyme may work less efficiently, allowing histamine to build up and potentially contribute to symptoms such as allergies, migraines, skin reactions, and digestive discomfort.

Practical considerations

  • Consider a low histamine eating pattern by limiting or avoiding aged cheeses, processed or cured meats, fermented foods and beverages, certain fish that are not fresh, and leftovers that have been stored for long periods.
  • Include fresh, minimally processed foods. Favor freshly cooked proteins and vegetables that are low in histamine.
  • Support methylation with nutrients such as SAMe, methylfolate, and magnesium after discussing with your healthcare provider.
  • Work on stress reduction strategies and prioritize regular, sufficient sleep to support enzyme function and immune balance.
  • If symptoms are significant, discuss with your provider the option of measuring histamine, DAO activity, and related labs to build a complete picture.
One effect allele (CT) — moderately reduced HNMT activity

If your genotype is CT for rs11558538 you carry one copy of the effect allele and one copy of the non-effect allele. This genotype is associated with slightly reduced HNMT activity and a moderate increase in the likelihood of histamine intolerance. The enzyme may work somewhat less efficiently, which could permit some histamine accumulation and contribute to symptoms like allergies, headaches, or milder digestive complaints.

Practical considerations

  • Adopt a sensible low-histamine approach when you notice symptoms. Avoid or limit known high-histamine foods such as aged cheeses, fermented products, wine, beer, and processed meats.
  • Keep food fresh. Avoid eating leftovers that have been stored for long periods and freeze protein portions if you will not use them within a day or two.
  • Support methylation with dietary sources of folate, B12, and magnesium. Discuss supplement options such as SAMe or methylfolate with your healthcare provider if appropriate.
  • Identify and minimize personal triggers including certain medications, alcohol, or prolonged stress.
  • If symptoms are persistent, speak with your provider about targeted testing and a personalized plan.
No effect alleles (CC) — typical or increased HNMT activity

If your genotype is CC for rs11558538 you have two copies of the non-effect allele. This genotype is associated with typical or enhanced HNMT activity and lower odds of histamine intolerance. Your HNMT enzyme is likely efficient at methylating and deactivating histamine, which helps maintain balanced histamine levels and reduce susceptibility to histamine-related symptoms.

Practical considerations

  • Many standard dietary and lifestyle strategies remain valuable. Maintain a balanced diet, adequate sleep, stress management, and regular physical activity.
  • If you experience histamine-like symptoms, consider other causes such as dietary histamine load, intestinal DAO activity, medication effects, or unrelated conditions and consult your provider for assessment.
  • Continue to monitor reactions to aged and fermented foods; even with efficient HNMT some people are sensitive to high dietary histamine.

Dietary and Food Strategies

  • Low histamine focus: limit aged cheeses, fermented foods and beverages, processed and cured meats, smoked or canned fish, and alcohol, especially red wine and beer.
  • Choose fresh proteins and prepare food fresh when possible. Freeze portions to prevent histamine buildup in leftovers.
  • Avoid foods that commonly trigger personal symptoms. Common culprits include tomatoes, eggplant, spinach, strawberries, and citrus for some people.
  • Support gut health with fiber-rich vegetables, prebiotic foods, and a balanced intake of probiotics only after discussing with your provider, since some probiotic strains can raise histamine.

Supplement Considerations

  • SAMe (S-adenosylmethionine): may support methylation pathways that help HNMT function. Use only after discussing risks and dosing with a healthcare provider.
  • Methylfolate and methylcobalamin (B12): support methylation and homocysteine metabolism. Provider consultation is recommended before starting.
  • Magnesium: supports many enzymatic reactions and can be beneficial if intake is low. Choose food sources first and discuss supplementation with your provider.
  • DAO enzyme supplements: these act in the digestive tract to break down dietary histamine and may help with food-related symptoms. Talk to your provider before starting.
  • Antihistamines and other medications: these can control symptoms short term but are not a substitute for addressing root causes. Use only under guidance from your healthcare provider.

Lifestyle and Monitoring

  • Stress management: chronic stress can affect immune balance and may influence histamine-related symptoms. Practice regular stress reduction techniques such as breathing exercises, mindfulness, or moderate exercise.
  • Sleep: aim for consistent, sufficient sleep to support overall enzyme activity and immune regulation.
  • Track symptoms and triggers: keep a food and symptom diary to help identify patterns and personal triggers.
  • Work with your healthcare provider: if symptoms are moderate to severe, ask about testing for blood histamine, diamine oxidase activity, nutrient levels, and other labs to guide care.

When to Contact a Healthcare Provider

Always consult your healthcare provider if you have persistent or severe allergies, unexplained headaches or digestive symptoms, or any new concerning health changes. Genetic information can guide lifestyle and preventive strategies but does not replace clinical evaluation, diagnosis, or treatment.

Important Disclaimer

PlexusDx provides genetic education and information only. This content is not medical advice. Genetic results do not diagnose conditions or substitute for professional medical care. Speak with your healthcare provider before making changes to diet, supplements, or medications. Your provider can interpret genetic results in the context of your personal health history and current medical needs.