Is Histamine Intolerance Genetic? Understanding DAO & HNMT Enzyme SNPs

Category : Functional Medicine, Histamine Intolerance / MCAS

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.

It’s important to distinguish histamine intolerance from histamine intoxication. Histamine intoxication is a form of food poisoning caused by consuming foods with excessively high histamine levels, such as spoiled fish or certain cheeses, whereas histamine intolerance results from the body’s inability to efficiently degrade histamine, often due to enzyme deficiencies.

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.

The main histamine metabolic pathways in humans involve the enzymatic degradation of both endogenous histamine (produced by the body’s own cells) and exogenous histamine (from dietary sources) by diamine oxidase (DAO) and histamine-N-methyltransferase (HNMT).

DAO primarily acts on exogenous histamine in the gut, while HNMT metabolizes endogenous histamine in tissues, helping regulate histamine’s physiological and pathological effects. I realize that’s a lot of SNPS!

The main symptoms of histamine intolerance include flushing, diarrhea, nausea, headache, and shortness of breath. Gastrointestinal symptoms can include bloating, abdominal pain, diarrhea, and constipation, while skin symptoms such as eczema, urticaria, and flushing may also occur. The symptoms of histamine intolerance can mimic those of allergic reactions, making diagnosis challenging.

Read: Histamine Intolerance: Could This Be Another Reason Why You Are Sick?

Introduction to Histamine Intolerance

Histamine intolerance is a complex condition that arises when there is an imbalance between the amount of histamine consumed or produced in the body and the body’s ability to break it down efficiently. This imbalance can result in a wide range of symptoms, including digestive discomfort, skin reactions, and respiratory issues.

At the heart of histamine intolerance is the enzyme diamine oxidase (DAO), which is responsible for breaking down histamine in the gastrointestinal tract.

When DAO activity is reduced—whether due to genetic factors, gut health issues, or other influences—histamine can accumulate, leading to elevated histamine levels and the onset of histamine intolerance symptoms.

Histamine itself is a biogenic amine that plays a crucial role in the body’s immune response, gastric acid secretion, and acts as a neurotransmitter. It exerts its effects by binding to four different histamine receptors (H1, H2, H3, and H4), each of which is distributed throughout various tissues and is responsible for different physiological responses. For example, the H1 receptor is involved in mediating allergic reactions and inflammation, while the H2 receptor regulates gastric acid secretion in the stomach.

Symptoms of histamine intolerance often mimic those of allergic reactions and can include headaches, abdominal pain, skin rashes, hives, and respiratory difficulties. Because these symptoms overlap with other conditions such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), diagnosing histamine intolerance can be challenging.

Is Histamine Intolerance and Allergy?

Many individuals with suspected histamine intolerance are compared to those with food allergies or other forms of food intolerance, but the underlying mechanism is distinct—centered on the body’s ability to degrade histamine rather than an immune-mediated response.

A low histamine diet is commonly recommended as an initial strategy to help manage symptoms. This approach involves reducing the intake of high histamine foods, such as fermented foods, aged cheeses, and certain fish, to help prevent excess histamine accumulation.

In addition to dietary management, understanding genetic variations—specifically single nucleotide polymorphisms (SNPs) in the DAO gene—can provide valuable insights.

Genetic testing can identify individuals who may have reduced DAO enzyme activity due to these genetic variants, making them more susceptible to histamine intolerance.

The Genetics Of Histamine Intolerance. Understanding DAO & HNMT Enzyme SNPS — Think you have a problem with Histamine Intolerance or MCAS? Take the Quiz here

In summary, histamine intolerance is a multifaceted condition that requires a comprehensive approach to both diagnosis and management. By understanding the role of the DAO enzyme, the impact of dietary histamine, and the influence of genetic variations on histamine metabolism, individuals can take proactive steps to manage their symptoms and improve their quality of life.

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 symptoms can be influenced by gut health, diet, and the composition of the gut microbiome. Dietary factors, such as fermented foods and other high-histamine foods, can trigger or exacerbate histamine symptoms.

Histamine intolerance is a condition characterized by the impaired ability to properly metabolize histamine, a chemical naturally present in the body. Histamine is produced by the body’s own cells (endogenous histamine) and can also be ingested from foods.

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.

Some individuals may develop histamine intolerance over time due to changes in gut health, enzyme activity, or other factors.

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

Comprehensive Histamine Support Protocol — Need a Comprehensive Support Protocol for histamine Overload?

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.

Human diamine oxidase activity can vary due to genetic differences in the diamine oxidase gene, and over 50 genetic variations (SNPs) have been identified, some of which reduce enzyme function.

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. DAO deficiency is also associated with various functional gastrointestinal disorders, including irritable bowel syndrome and non-celiac gluten sensitivity.

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 offer relief from headaches, digestive issues, and skin reactions.

Serum enzyme activity, specifically diamine oxidase serum activities, can be measured in blood samples to assess DAO function, though the clinical utility is debated.

Other biogenic amines, such as tyramine and putrescine, can also be present in foods and may inhibit DAO activity, potentially worsening symptoms.

HNMT (Histamine N-Methyltransferase) Enzyme:

Histamine N-methyltransferase (HNMT) is the primary enzyme responsible for breaking down histamine in the central nervous system, where it acts mainly on intracellular histamine. HNMT is present in various tissues throughout the body, including the liver, kidneys, central nervous system, and lungs.

The histamine n methyltransferase (HNMT) enzyme is involved in the methylation process of histamine, converting it into its inactive form for excretion.

By targeting intracellular histamine, HNMT plays a central role in regulating histamine activity within tissues and cells, as well as maintaining overall histamine levels in the brain and peripheral nervous system (*),(*).

Genetic SNPS in DAO or HNMT can alter the balance of histamine levels in the body, contributing to histamine intolerance symptoms. For example, the HNMT C314T genotype can reduce enzyme activity by 30–50%, increasing the risk of neurological symptoms such as migraines or asthma.

Genetic Testing for the DAO or HNMT SNPs can be a key to identifying why you struggle with histamine intolerance and MCAS.

Signs You Have A Problem with DAO or HNMT

Specific symptom combinations are often used to evaluate and diagnose histamine intolerance, as individuals who are histamine intolerant may experience a range of gastrointestinal symptoms. Common gastrointestinal symptoms include bloating, abdominal discomfort, gas, diarrhea, and constipation. A study found that 92% of patients with histamine intolerance reported abdominal distension(*).

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

Histamine intolerance can also lead to symptoms such as dizziness, headaches, and palpitations, indicating involvement of the nervous and cardiovascular systems.

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.

DAO deficiency can result from genetic variations in the DAO gene, and over 50 genetic variations (SNPs) in the DAO gene have been identified—some of which reduce enzyme function and increase the risk of histamine intolerance.

Histamine intolerance can be caused by both primary (genetic) factors, such as DAO gene mutations, and secondary factors, such as medications or inflammatory bowel diseases. Primary histamine intolerance is due to genetic factors, while secondary intolerance develops from gut issues or medications that impair DAO function.

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 DAO and HNMTenzymes, 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. In fact, blood samples are used in laboratory tests to diagnose histamine intolerance by measuring DAO activity and total histamine concentration. Unfortunately, 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.

The determination of plasma DAO activity is a proposed diagnostic approach for histamine intolerance, though its validity is still debated. Because it is still too early and not enough research supports this correlation, I do not recommend Serum DAO testing at this time.

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.

Too much histamine in the body can lead to symptoms like headaches, heart palpitations, and digestive issues, so maintaining balanced histamine levels is important for overall health.

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.

Whats Causing Histamine Intolerance-The Histamine Bucket

The bucket can overflow due to a variety of reasons, including high histamine intake from certain foods (e.g., aged cheese, fermented foods), which have the highest histamine content because histamine is produced in food primarily during maturation and fermentation processes.

Other factors include medications that release histamine or block its breakdown (e.g., some painkillers, certain antidepressants), allergic reactions food, hormonal fluctuations, infections and even stress.

Histamine release from mast cells in response to allergens, infections, or stress, followed by histamine degradation by enzymes like DAO and HNMT, are key processes that help prevent higher histamine plasma levels and the resulting symptoms.

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.

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

Supplementation:

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

Histamine Quiz — Take the Histamine Intolerance/MCAS 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.

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.

The histamine 50-skin-prick test has been suggested as a diagnostic tool for histamine intolerance, as it can indicate reduced histamine degradation ability. 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, such as the skin prick test to rule out IgE-mediated food allergies, 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.