HNMT Thr105Ile (rs1050891): Histamine Methylation

HNMT (Histamine N-Methyltransferase) is the primary enzyme for degrading histamine inside cells, particularly in the brain and airways. Unlike DAO which works in the gut, HNMT handles histamine that's already entered tissues. The Thr105Ile variant (rs1050891) affects enzyme activity with implications for neurological symptoms, allergies, and inflammation.

Understanding HNMT

HNMT provides the intracellular pathway for histamine inactivation:

• Mechanism: Adds a methyl group to histamine, converting it to N-methylhistamine
• Location: Inside cells - brain, airways, skin, and other tissues
• Methyl donor: Uses SAM (S-adenosylmethionine) as the methyl source
• Key tissues: Especially important in brain and bronchial epithelium

HNMT vs. DAO: Two Pathways

Understanding Your Genotype

• C/C (Thr/Thr): Normal HNMT activity
• C/T (Thr/Ile): Reduced activity - approximately 30% decrease
• T/T (Ile/Ile): Further reduced activity

The isoleucine (Ile) substitution reduces enzyme efficiency, leading to slower histamine methylation.

Brain and Neurological Effects

HNMT is crucial for brain histamine regulation. Reduced activity may manifest as:

Cognitive and Mood Symptoms

• Sleep disturbances: Histamine promotes wakefulness; excess may cause insomnia
• Anxiety: Brain histamine influences anxiety circuits
• Difficulty concentrating: High histamine can cause mental fog and distractibility
• Motion sickness: Histamine is involved in vestibular function
• Appetite changes: Brain histamine regulates satiety

Why Antihistamines Cause Drowsiness

First-generation antihistamines (like diphenhydramine) cross into the brain and block histamine - causing sedation. This demonstrates histamine's role in maintaining alertness. Those with HNMT variants may have higher baseline brain histamine, which could affect sleep-wake regulation.

Respiratory and Allergy Effects

HNMT is highly expressed in bronchial tissue:

Asthma Connection

• Studies link the Ile allele to increased asthma risk
• Reduced histamine clearance in airways may prolong bronchospasm
• May influence response to asthma medications
• Allergic asthma may be more severe with reduced HNMT

Allergic Rhinitis

• Prolonged nasal symptoms after allergen exposure
• May explain why some people have persistent congestion
• Antihistamines may be particularly helpful for carriers

The Methylation Connection

HNMT requires SAM (S-adenosylmethionine) to function. This links it to overall methylation:

Methylation Demands

• HNMT competes with other methylation reactions for SAM
• If overall methylation is compromised (MTHFR variants), HNMT may be affected
• Adequate folate, B12, and B6 support SAM production
• Methylation support may indirectly help HNMT function

Supporting HNMT Through Methylation

• Folate/methylfolate: Supports SAM production
• Vitamin B12: Essential for methylation cycle
• Vitamin B6: Involved in SAM synthesis
• TMG (betaine): Alternative methyl donor
• SAMe supplements: Direct HNMT cofactor (use cautiously)

When Both DAO and HNMT Are Affected

Having variants in both pathways creates a "double hit":

• DAO variants: Dietary histamine enters the body more easily
• HNMT variants: Once inside, histamine is cleared more slowly
• Result: Higher histamine levels in tissues and more severe/prolonged symptoms

This combination may explain why some people have severe histamine intolerance while others with just DAO or HNMT variants have milder issues.

Prevalence

• European ancestry: T allele (Ile) frequency approximately 10-15%
• Asthma studies: Consistent association in multiple populations
• Asian populations: Higher frequency in some studies

Management Strategies

For Neurological Symptoms

• Consider overall histamine load from diet
• Support methylation through B vitamins
• Address sleep hygiene - histamine affects circadian rhythm
• Some find H1 antihistamines helpful for sleep (consult doctor)

For Respiratory Symptoms

• Work with allergist/pulmonologist for asthma management
• Antihistamines may be particularly effective
• Environmental controls to reduce allergen exposure
• Consider low-histamine diet during allergy season

Supplements to Consider

• Quercetin: Natural antihistamine and mast cell stabilizer
• Vitamin C: Supports histamine degradation
• B vitamins: Support methylation for HNMT function
• Magnesium: Natural mast cell stabilizer

Testing with NutraHacker

NutraHacker's Histamine Panel analyzes both HNMT variants (rs1050891 and rs11558538) alongside AOC1/DAO variants, providing a complete picture of both histamine degradation pathways.

Frequently Asked Questions

Can I take SAMe to support HNMT?

SAMe supplements can provide the methyl donor HNMT needs. However, SAMe can also be stimulating for some people and may affect mood. Start with low doses if trying it, and consult with a healthcare provider, especially if you have mood disorders or are taking medications.

Why do antihistamines make me drowsy if I have high brain histamine?

First-generation antihistamines block histamine receptors in the brain, which causes drowsiness because histamine normally promotes wakefulness. Non-drowsy antihistamines (cetirizine, loratadine) don't cross the blood-brain barrier as readily, so they're better for daytime use.

Does this affect my response to allergy medications?

Potentially. If you have reduced HNMT activity, you may benefit more from antihistamines because your body clears histamine more slowly. Some people with this variant report that antihistamines seem particularly effective for them.

References

1. Preuss CV, et al. Histamine N-methyltransferase gene polymorphisms and their impact on allergic diseases. Clin Exp Allergy. 2010;40(10):1434-1436.
2. Kennedy MJ, et al. Histamine and histamine intolerance. Am J Clin Nutr. 2007;85(5):1185-1196.
3. Yan L, et al. Association of histamine N-methyltransferase Thr105Ile polymorphism with asthma susceptibility: a meta-analysis. J Investig Allergol Clin Immunol. 2012;22(4):257-262.