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The Genetics Of Histamine Intolerance. Understanding DAO & HNMT Enzyme SNPs

When you have Histamine Intolerance or Mast Cell Activation Syndrome (MCAS), Genetic Analysis and understanding the genetics of histamine intolerance including the DAO and HNMT SNPS can be some of the most powerful tools used.

In today’s article, I want to shed some light on the Genetics of Histamine Intolerance. Specifically, I want to help you understand more about the DAO SNPs and the HNMT SNP. If you don’t know what a SNP (SNIP) is, don’t worry as I will explain what they are in easy-to-understand English, I will also review what SNPs  (SNIPS) are involved in Histamine Intolerance, what happens when you have SNPs in the DAO enzyme or HNMT enzyme and the impact these SNPs have on histamine metabolism. I realize that’s a lot of SNPS!

The Genetics Of Histamine Intolerance. Understanding DAO & HNMT Enzyme SNPS

Histamine Refresher

Let’s do a quick refresher just in case you are feeling a bit rusty when it comes to Histamine. Histamine is a compound released by the immune system that is primarily recognized for its involvement in allergic reactions. (*) However, this biologically active molecule serves additional vital purposes, such as regulating the sleep-wake cycle, digestion, breathing, and cognitive function.

Histamine intolerance is a condition characterized by the impaired ability to properly metabolize histamine, a chemical naturally present in the body. Around 80% of patients affected by histamine intolerance are female, and between 25 and 45 years old. Women who are affected by histamine intolerance, often report a cycle-dependency of their symptoms, so a link to sex hormones is assumed. (*),(*)

When someone has histamine intolerance, they may experience a variety of symptoms, such as migraines, hives, digestive issues, respiratory problems, severe PMS with painful periods, anxiety, and a host of mental health problems. Much of this depends on what histamine receptors (H1, H2, H3, H4) histamine is binding to and If the individual has a genetic SNP in the DAO or HNMT enzyme.

The Genetics Of Histamine Intolerance. Understanding DAO & HNMT Enzyme SNPS

Think you have a problem with Histamine Intolerance or MCAS? Take the Quiz here

DAO (Diamine Oxidase) Enzyme:

DAO is primarily found in the small intestine, particularly in the cells lining the intestinal mucosa. DAO is responsible for metabolizing and breaking down histamine that is ingested through food or produced in the gut. The DAO enzyme helps prevent histamine accumulation in the digestive system, which can otherwise lead to symptoms such as bloating, diarrhea, abdominal pain, or allergic-like reactions.

SNPs in DAO genes can result in reduced DAO activity, leading to compromised histamine breakdown. This can cause elevated histamine levels, leading to symptoms associated with histamine intolerance.

Diamine oxidase (DAO) supplements are over-the-counter products that restore the diamine oxidase enzyme in your body. They help break down histamine-rich foods and may reduce symptoms of histamine intolerance. Research shows that these supplements might offer relief from headaches, digestive issues, and skin reactions

HNMT (Histamine N-Methyltransferase) Enzyme:

HNMT is present in various tissues throughout the body, including the liver, kidneys, central nervous system, and lungs. HNMT enzyme is involved in the methylation process of histamine. It helps convert histamine into its inactive form, which can then be excreted from the body. HNMT enzyme plays a key role in regulating the overall histamine levels in the brain and peripheral nerve system. (),(*).

Genetic SNPS in either the DAO or HNMT can alter the balance of histamine levels in the body, contributing to histamine intolerance symptoms. Genetic Testing for the DAO or HNMT SNPs can be a key to identifying why you struggle with histamine intolerance and MCAS.

The Genetics Of Histamine Intolerance. Understanding DAO & HNMT Enzyme SNPS

Signs You Have A Problem with DAO or HNMT

  • Histamine problems
  • Food sensitivity, seafood, or reheated foods
  • Intolerant of red wine or alcohol
  • Intolerance to fermented foods like cheese
  • Frequent nose bleeds
  • Headaches or migraines
  • Depression
  • Anxiety
  • TICS
  • Insomnia
  • Irritable bowel issues, such as diarrhea, and SIBO
  • Leaky gut syndrome
  • Health is better during pregnancy (including ability to digest food)
  • Skin stays red for longer than normal after getting scratched
  • Eczema
  • Frequently feel itchy
  • Heartburn or acid reflux
  • Frequently need antihistamines
  • Near-constant congestion or runny nose
  • Sleep problems
  • Panic Attacks
  • Low blood pressure
  • Joint pain
  • Frequently experience worse-than-normal side effects from medications
  • Sensitivity to dust mites

The Genetics Of Histamine Intolerance. Understanding DAO & HNMT Enzyme SNPS

Genetics of Histamine Intolerance

Genetic SNPs, which stands for Single Nucleotide Polymorphisms, and pronounced as SNIPS, are like tiny variations or differences in our DNA code. Our DNA acts like a blueprint that contains instructions for our bodies on how to function. These SNPs are changes that occur in just one single component of our DNA sequence.

Think of it like a book where each letter represents a piece of genetic information. If a SNP happens, it’s like changing one letter in a word. This alteration might not impact the entire story, but it could affect how a specific chapter plays out.

These genetic variations can influence things like our physical characteristics, how our bodies process nutrients, and even how we respond to certain medications. By studying these SNPs, and understanding what SNPs we may have, a Functional Medicine Practitioner can make more personalized health car care recommendations that impact your well-being.

While we can have genetic SNPs in many different genes that affect our health, today I want to zero in on the genetics of histamine intolerance and the genetic SNPs that have been identified in histamine intolerance/MCAS.

SNPs in the genes encoding the DAO, and HNMT enzymes, are important when it comes to breaking down histamine in the body. In the case of histamine intolerance and MCAS symptoms, genetic tests can be carried out to see whether variations in the genes that are jointly responsible for histamine breakdown in the body.

AOC1, or Amine Oxidase Copper Containing 1

AOC1, or Amine Oxidase Copper Containing 1, is a genetic variant seen in histamine intolerance. This gene is responsible for the production of the DAO enzyme.  If you carry a ‘faulty’ version of the AOC1 gene, then less DAO is produced, leaving you predisposed to histamine intolerance/MCAS and allergic reactions. (*)

Certain genetic variations in the DAO gene, in the sequence variants rs2052129, rs2268999, rs1049742, and rs10156191, are associated with reduced DAO activity.(*),(*),(*)

In addition to diamine oxidase (DAO) breaking down histamine, there is another enzyme that can degrade histamine. This enzyme is Histamine N-Methyltransferase, or HNMT. The HNMT C314T genotype results in a 30-50% reduction in histamine methyltransferase activity and is more common in people with aspirin intolerance.(*),(*)

Depending on the things “filling up your histamine bucket”, the treatment approache when you have  differ. In the case of genetic variants in the DAO and HNMT enzymes, it is often sensible to ensure that the histamine-degrading enzymes DAO and HNMT are not additionally blocked in their activity by certain medications.

Learn which drugs/medications affect DAO and HNMT enzyme here

Testing DAO in Blood

As I have been discussing, Diamine oxidase (DAO) primarily functions to metabolize histamine that is ingested. This enzyme is located within the intestinal mucosa of the gastrointestinal tract. Like many tests, you would think that we can just test someone DAO levels in their blood. Unfortunatly, while this practice is done by some providers, the existing guidelines pertaining to histamine sensitivity do not view this assessment and these tests as adequately supported by scientific evidence and, therefore, do not endorse its use.

At present, it remains uncertain to what degree the blood-based DAO levels or activity correspond to the functioning and presence of diamine oxidase in the intestines, where the enzyme is predominantly responsible for breaking down biogenic amines.

Certain studies have reported that individuals in the control group exhibited DAO levels below the defined threshold, despite not manifesting symptoms of histamine sensitivity. Additionally, the reliability of blood-based DAO measurements as a diagnostic tool for identifying individuals susceptible to symptoms following histamine ingestion varies across different research findings, casting doubt on the overall utility of such tests. Because it is still too early and not enough research supports this correlation, I donot recomend Serum DAO testing at this time.

The Genetics Of Histamine Intolerance. Understanding DAO & HNMT Enzyme SNPS

What’s Filling Up Your Histamine Bucket?

Imagine your body as a bucket. This bucket represents your body’s capacity to tolerate and process histamine. In a healthy individual, the bucket has a certain capacity to handle incoming histamine from various sources, such as the food we eat, the environment, and the body’s own production of histamine.

However, in some individuals, this bucket might be smaller or overloaded due to various factors, such as genetic SNPS in the DAO and HNMT enzyme, gut issues like leaky gut, SIBO, or inflammatory bowel disease, or other underlying conditions. When the incoming histamine exceeds the capacity of the bucket, it starts to overflow, leading to symptoms associated with histamine intolerance or sensitivity.

The bucket can overflow due to a variety of reasons, including high histamine intake from certain foods (e.g., aged cheese, fermented foods), medications that release histamine or block its breakdown (e.g., some painkillers, certain antidepressants), allergic reactions food, hormonal fluctuations, infections and even stress.

The histamine bucket analogy helps to illustrate that by reducing the amount of histamine entering the bucket and supporting the body’s ability to process histamine (e.g., through enzyme support or gut health improvement), symptoms can be better managed.

The Genetics Of Histamine Intolerance. Understanding DAO & HNMT Enzyme SNPS

Histamine Management Strategies:

Understanding genetic SNPs in the DAO and HNMT enzymes can help you’re your Functional Medicine Doctor to personalize their management and treatment strategies.

These may include:

Low Histamine Diet:

A low histamine diet involves avoiding or limiting histamine-rich foods, which helps reduce histamine intake from external sources. This can complement the body’s decreased ability to metabolize histamine due to genetic variants in the DAO and HNMT enzyme.

Learn more on How to start a Histamine Diet here Part I and Part II


Certain supplements, are beneficial for individuals who have genetic SNPS in DAO and HNMT enzymes. These supplements aim to

  • Support histamine breakdown
  • Supply the DAO enzyme
  • Stabilize Mast Cells
  • Provide nutrient cofactor to help enzyme function.

Read more about My Histamine Supplement Support Pack, here

Lifestyle Adjustments:

Managing stress and cortisol levels, getting sufficient sleep, and improving your gut microbiome, optimizing your hormone levels, addressing Mold and mold biotoxins, etc can also contribute to reducing histamine intolerance symptoms.

Histamine Quiz

 Take the Histamine Intolerance/MCAS Here

Here’s What You Should Remember About Today’s Article on Genes Associated with Histamine Intolerance 

Genetic SNPs associated with the DAO and HNMT enzymes have been linked to histamine intolerance and its symptoms. Understanding Genetics of Histamine Intolerance can help individuals with histamine intolerance personalize their management strategies, such as following a low histamine diet, considering supplementation, and making lifestyle adjustments.

It’s important to note that histamine-related disorders can be complex and require proper diagnosis and management under the guidance of a healthcare professional, such as an allergist, immunologist, and Certified Functional Medicine Practitioner. They can provide appropriate testing, identify potential enzyme deficiencies or dysfunctions, and develop personalized treatment approaches, which might include dietary modifications, enzyme supplementation, or other interventions.

Genetic testing and consultation with a Certified Functional Medicine Practitioner can be essential for accurate analysis and tailored recommendations when you have Histamine Intolerance/MCAS. By addressing these genetic factors, Diet, Gut Health, Hormones and some of the other factors filling up your histamine bucket, individuals with HIT and MCAS can better manage their histamine intolerance and improve their overall quality of life.

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