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Histamine, Metabolism, & Your Genetics

Updated: Feb 17

A high-histamine diet and certain lifestyle choices can lead to histamine intolerance and widespread symptoms. But is it really that simple? Or are there some other underlying issues that may interfere with histamine metabolism and lead to histamine intolerance.

You are right. The issue may be more complex. Your genes may play a role too. In certain people, there is a link between histamine intolerance and genetics. Certain gene variations can interfere with your body’s ability to break down histamine effectively and/or cause your body to make more histamine. Uncovering a genetic variability may be the missing piece of your histamine intolerance puzzle.

Today I want to discuss the connection between histamine intolerance and genetics. Let’s get into it.

What Is Histamine Intolerance

Before we get into the connection between histamine intolerance and genetics, I want to go over what histamine and histamine intolerance are.

What Is Histamine

Histamine is naturally made by your body to support your immune system and various mechanisms inside your body. It helps your body to get rid of allergens and toxins. Histamine also triggers the release of hydrochloric acid for digestion and gut health. It also plays the role of a neurotransmitter and supports your brain and mental health.

No doubt, histamine is essential for your health and wellness. Too much histamine in your body, however, can turn into a serious issue. Too many high-histamine foods, environmental toxins, stress, and other factors can increase the histamine load in your body. It may become too much for your body to deal with. If your body cannot break down histamine, it can lead to histamine intolerance. Histamine intolerance is essentially a buildup of histamine. Histamine intolerance can affect your entire body and can lead to widespread symptoms.

Symptoms of Histamine Intolerance

Symptoms of histamine intolerance may be anywhere from mild to severe. They can be widespread and seemingly separate from each other. Though some people may only experience one or a few of these symptoms, you may be one of those unlucky folks who can recognize all symptoms on this list.

As you will later learn, symptoms of histamine intolerance and genetics can be connected. Certain genetic variances and mutations may trigger specific symptoms of histamine intolerance.

Symptoms of histamine intolerance may include:

  • Headaches and migraines

  • Eczema, dermatitis, acne, and other skin issues

  • Hives

  • Fatigue and sleep issues

  • Red eyes

  • Dizziness or vertigo

  • Heart palpitation or racing heart

  • Brain fog, confusion, memory issues

  • Irritability and mood swings

  • Anxiety or panic attacks

  • Blood pressure changes

  • Allergies

  • Asthma

  • Congestion or runny nose

  • Acid reflux, bloating, diarrhea, and other digestive symptoms

  • Abnormal menstrual cycle and premenstrual syndrome (PMS)

Too Much Histamine or Not Enough Enzymes?

Though there are many underlying triggers for histamine intolerance, from diet to toxins, there are two main causes: too much histamine or not enough enzymes. You may experience only one or both of these problems. In the later section, you will learn how these underlying issues of histamine intolerance and genetics may be connected, but first, let’s see how too much histamine and not enough enzymes can cause histamine issues.

Too Much Histamine

Your body may have too much histamine due to a high-histamine diet for a variety of reasons. Following a high histamine diet, environmental toxins, stress, certain medications, too many histamine-producing microbes in your gut, and mast cell activation issues can also add to your histamine bucket and lead to histamine intolerance. Even if your body has enough enzymes to break down a normal amount of histamine, it will have difficulty dealing with this.

Not Enough Enzymes

A normal body produces enzymes to break down histamine. Diamine oxidase (DAO) is an enzyme made by your body to break down excess histamine from food. It is made in the villi lining of your small intestines. Thus, gut health issues can lead to problems with DAO production. If your body doesn’t make enough DAO enzymes, it can lead to DAO deficiency and histamine intolerance (1).

Histamine N-methyltransferase (HNMT) is another enzyme involved in histamine metabolism. It helps to deactivate and break down histamine made by your body. It specifically plays an important role in breaking down histamine in your brain and helps to reduce the risk of neurodegenerative disorders, mental health issues, and migraines (2).

Your 4 Histamine Receptors and Their Function

So why does histamine intolerance cause such widespread symptoms? Understanding the role and function of your different histamine receptors may explain the different actions and effects of histamine in your body. Basically, the action of histamine depends on which histamine receptor it binds to, and in what part of your body (3). Since genetic factors can impact your histamine receptors, too, it’s important that you understand the function of each histamine receptor first. Once you understand this, we can move on to the connection between histamine intolerance and genetics.

H1 Receptor

H1 histamine receptors are found in your smooth muscle, central nervous system, endothelial cells, and mast cells. If your H1 receptors get activated, it can cause allergy symptoms, such as itching, runny nose, swelling, skin reactions, and vasodilation, as well as asthmatic reactions.

H2 Receptor

H2 histamine receptors can be found in your stomach, intestinal tract, walls of your blood vessels, and mast cells. Activating H2 receptors in your stomach can lead to stomach acid release. In your mast cells, it will lead to histamine release. In your heart, it can cause heart rhythm changes.

H3 Receptors

H3 histamine receptors are found in your central and peripheral nervous systems. Activating the H3 receptors can cause a release of serotonin, norepinephrine, and acetylcholine, impacting your mental and brain health (4).

H4 Receptors

H4 histamine receptors can be found in your bone marrow, basophils, small intestine, thymus, colon, spleen, and mast cells. Activating the H4 receptors is the core cause of the inflammatory response in your body and can lead to all kinds of inflammatory reactions (5).

A Combination of Issues

Your histamine issues may be related to issues with or activation of several different histamine receptors. According to a 2006 study published in Gut, people with irritable bowel syndrome (IBS) and/or food allergies seem to have much higher amounts of H1 and H2 receptors in their gut than people without these issues (6).

Histamine Intolerance and Genetics

Now that you understand what histamine is and how it works in your body, we can dig in to see how histamine intolerance and genetics may be connected. Let’s look at how your genetics can influence histamine intolerance.

DAO Enzyme

As you know, the DAO enzyme plays an important role in breaking down histamine from food. Problems with DAO enzyme production can cause an inefficient breakdown of histamine and consequent histamine intolerance symptoms. Genetic variants in the AOC1 gene can lead to both an increase or a decrease in DAO production (7, 8). Too little DAO can, of course, lead to an inefficient breakdown of histamine and histamine intolerance.

It’s not only genetics that can slow DAO enzyme production. Enzyme production and enzyme activity can decline with age (9). Combined with other age-related phenomena, including estrogen dominance, you may have a serious issue on your hands.


Histamine and estrogen attach to the same H1 receptor. As a result, estrogen triggers your mast cells to release histamine from your reproductive organs. If you have too much estrogen (estrogen dominance), it will lead to increased histamine release (10, 11). If you already have slow DAO enzyme production due to aging, genetic problems, or other factors, your body will have an even more difficult time taking care of excess histamine. This may lead to a vicious cycle of histamine intolerance and estrogen dominance.

HNMT Gene

HNMT is another enzyme that helps to break down histamine. It is responsible for about 80% of histamine breakdown in your body (12). However, genetic variations in the HNMT gene can result in issues, including a decrease in histamine breakdown and an increased risk of asthma symptoms (13, 14, 15, 16).

MTHFR Gene

MTHFR is an enzyme in your body responsible for a variety of chemical reactions in your body. It plays a critical role in methylation, which is the process of converting folate (vitamin B9) into methyl-folate. Methylation is essential for optimal DNA cell function, processing hormones, repairing damaged cells, metabolizing B vitamins, regulating neurotransmitters, and detoxification. It is also necessary for making methyl groups that are necessary for the HNMT cycle. Issues with MTHFR can lead to an array of issues, from hormonal issues to mental health.

The methylation cycle also helps to break down monoamine neurotransmitters, such as histamine. Your MTHFR gene is responsible for making the MTHFR enzyme to support all these important functions of your body. Even though the MTHFR gene is incredibly important, MTHFR genetic mutations are very common. MTHFR mutations are single nucleotide polymorphisms (SNPs). One SNP stands for one difference in a single DNA building block. The more MTHFR SNP mutations, the more methylation issues and other health problems you may experience.

MTHFR mutations can lead to not only methylation problems but also a long list of health issues, including histamine intolerance, food intolerances, chemical sensitivities, allergies, hormonal issues, sleep problems, and mental health issues.

When it comes to histamine intolerance and MTHFR, we have to talk about the role of HNMT and S-Adenosyl-methionine (SAMe) as well. SAMe is a cofactor of HNMT and is essential for the formation, activation, and breakdown of various hormones, proteins, and drugs. Your body needs the MTHFR enzyme to produce SAMe. If there is an MTHFR genetic mutation, it can lower MTHFR function, interfere with SAMe production, and interrupt the HNMT function. This can lead to slower and ineffective histamine breakdown and removal, which can, of course, lead to histamine intolerance.

Furthermore, since methylation is essential for detoxification, MTHFR gene mutations and methylation issues may interfere with the ability to remove toxins from the body. Too many toxins can trigger your body and cause further histamine intolerance (17, 18, 19, 20).

HDC Gene

The HDC gene is responsible for encoding the histidine decarboxylase enzyme. Histidine is an amino acid found in many foods. It supports the repair of damaged tissues, the creation of blood cells, the health of your nerve cells, and growth. Your body also makes histamine from histidine. The histidine decarboxylase enzyme is essential for the conversion of histidine to histamine. HDC gene mutations can lead to a variety of problems, including histamine intolerance, allergic rhinitis, and inflammation (21, 22, 23).

Histamine Receptor Genes

Finally, you may also develop issues because of the genes that are necessary for your histamine receptors. The HRH1 gene is essential for the H1 receptor, HRH2 for the H2 receptor, and HRH4 for the H4 receptor. Mutations may increase asthma risks and allergies (24). HRH2 polymorphisms may affect the risk of gastritis and gastric cancer (25, 26). Reduced HRH4 activation increased the progression of non-small cell lung cancer (23).

Testing for SNPs

To uncover the potential connection between histamine intolerance and genetics in your body, genetic testing is your answer. Single nucleotide polymorphisms (SNPs, pronounced ‘snips’) are the most common form of genetic variation. Basically, when your cells divide into two, they copy their DNA into the new cells with genetic instructions. If these cells make mistakes, it can lead to variations in the DNA sequence. SNPs represent a difference in a single DNA building block (nucleotide) at a particular location. Since DNA is passed down from your parents, you can inherit SNPs from your parents.

Genetic testing through a blood or swab sample can test for SNPs and find certain genetic issues that may be behind your histamine intolerance. You can get tested for SNPs by your healthcare provider. However, these tests may not be covered by insurance and can cost a lot of money. You may also do it on your own. Genetic testing, like 23andMe offers standard testing for SNPs. Though they do not include all genetic SNPs, you can enter your results into a third-party company, such as StrateGene, to look for MTHFR or other genetic mutations that may be affecting your health. DNA Labs, based in Toronto, offers comprehensive SNP testing including a focus on methylation pathways and histamine removal.

Solutions for Histamine Intolerance and Genetic Problems

If you are experiencing symptoms of histamine intolerance, the first step you can take is to try a low-histamine diet.

Diet is the first step:

  • A low-histamine diet is your first step to reducing your levels of histamine. I recommend trying a low-histamine diet for at least a month to see if you feel better. After 1 to 3 months on a low-histamine diet, you can slowly reintroduce higher-histamine foods and see how you react.

  • If you are experiencing gut problems, you may also benefit from following a low-FODMAP diet for a short period until your gut heals.

  • You may benefit from mast cell-stabilizing foods, including watercress, moringa, chamomile, Thai ginger, apples, Brazil nuts, peaches, nettle, onion, fiber-rich foods, and quercetin-rich foods.

You may also benefit from certain supplements:

  • You may try supplementation with natural antihistamines and mast cell stabilizers, such as quercetin, resveratrol, curcumin, vitamin C, nettle leaf, and luteolin.

  • You may benefit from taking DAO supplements if you are deficient in the DAO enzyme.

  • If you have MTHFR gene variations and methylation issues, I recommend methylated B vitamins to ensure that your body can actually use it.

In addition to diet, I recommend reducing your histamine bucket through better lifestyle choices:

  • Practice good sleep hygiene and make sure to get 7 to 9 hours of quality sleep each night.

  • Reduce your stress levels. Practice meditation, mindfulness, breathwork, and gratitude. Spend plenty of time in nature.

  • Move your body regularly and exercise at least 5 days a week for 20 to 30 minutes.

  • Reduce exposure to toxins. Remove conventional, chemical-filled household, cleaning, hygiene, and beauty products. Choose organic, natural options instead. Reduce the use of plastic. Avoid smoking and second-hand smoke. Use an indoor air purifier and water purifier.

  • Consider avoiding medications that may trigger MCAS or increase histamine production.

  • Determine if you are estrogen dominant, and take steps to balance your sex hormones to avoid activating mast cells.

Next Steps

Do you want to learn more about histamine intolerance and genetics? Are you interested to see how your genetics may affect your histamine intolerance or mast cell activation problems? Working with a healthcare practitioner knowledgeable about histamine intolerance and MCAS is the best way to get to the root cause of your symptoms and create an individualized treatment. I welcome you to start a personalized functional medicine consultation with me for further guidance to improve your health. You may book your consultation here. Check out my Histamine Intolerance Course here. Learn on your own time, from anywhere. Get an inside look at the most helpful functional medicine tests for pinpointing imbalances, ways to identify and manage the most common (and sometimes surprising) mast cell triggers, and learn what to eat, what to avoid, and why.


1 Comment


Is it possible because I get hormone replacement treatment is that triggering more reaction to the high histamine intolerance

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