Histamine Intolerance and Your Genes

When your body has too much histamine, it can cause symptoms collectively known as histamine intolerance. This can be due to excess production of histamine by your body or not being able to break down histamine from foods very well. (Or both!)

Genetics plays a big role in how well your body breaks down histamine:

  • You can use your genetic data to figure out if your genes are part of the reason why you have histamine intolerance.
  • Knowing which genetic variants you carry leads to targeted solutions that are more likely to work for you.

 

What is Histamine Intolerance?

Classified as a biogenic amine, histamine is a molecule that plays many roles in the body.

Histamine’s many functions include:

  • causes allergic reactions,
  • acts within our immune defense system,
  • dilates blood vessels (vasodilatation)
  • acts as a neurotransmitter
  • works as a signaling molecule in the stomach to release acid

While most of us think of histamine only  during allergy season, histamine is a vital part of the way your body works.

This article get’s a bit long… stick with me.
Here’s a visual overview of where we are going here:

What are the symptoms of histamine intolerance?

Histamine intolerance symptoms impact many different systems in the body, including[ref]:

  • Head: headaches & migraines
  • Mood: anxiety, irritability, brain fog
  • Stomach: acid reflux, nausea, stomach pain
  • Intestines: bloating, diarrhea, constipation
  • Heart: heart arrhythmia, dizziness
  • Sinuses: drainage, congestion
  • Skin: hives, itching, flushing,
  • Sleep: insomnia, early waking

People with histamine intolerance usually have several of the symptoms above, but they won’t have all of the symptoms.[ref]

Historical note: Too much histamine has been known for decades to cause scombroid poisoning – the type of food poisoning from eating fish that isn’t fresh.[ref]

Causes of histamine intolerance:

The two main causes of histamine intolerance are:

  • not enough of the enzymes needed to break down histamine (DAO and HMNT)
    – and/or-
  • too much histamine being produced (gut microbes producing histamine, mast cells degranulating too easily, HDC variants, chronic exposure to allergens).

Breaking down histamine:

There are two ways that your body clears out histamine: using the DAO enzyme or using the HMNT enzyme.[ref]

1) Diamine oxidase (DAO) enzyme Histamine from foods or from bacteria in your gut is broken down using the DAO (diamine oxidase) enzyme. The DAO enzyme is produced in the villi lining the small intestines and released to metabolize histamine.[ref]

2) Histamine methyltransferase (HMNT) enzyme: The HMNT enzyme works throughout the body to deactivate and break down histamine created by your body. Thus, histamine that is used as a signaling molecule in the stomach or as a neurotransmitter in the brain will be broken down via a reaction that incorporates the HMNT enzyme.[ref]

Recent studies show exactly how important HNMT is in controlling brain histamine levels. Genetic variants that change HNMT levels in the brain are linked to an increased risk of Parkinson’s disease. Studies also link HNMT variants to an increased risk of migraines or ADHD.

Creation of Histamine:

The amino acid histidine is the precursor for histamine. It is an essential amino acid, meaning that we have to get it from food because we can’t synthesize it in the body. Histidine can be used in the body for several different purposes – including creation of histamine.

Histidine decarboxylase (HDC gene) is the enzyme that catalyzes the reaction of histidine into histamine. It does this inside various different cell types, including in large amount in mast cells.

histidine -> histamine (PMC7463562)

Not enough histamine:
What happens if you don’t have enough histidine decarboxylase? Animal studies show that if you reduce histidine decarboxylase, the animals have behavior that resembles Tourette syndrome. Genetics studies show that people with Tourette’s (vocal and motor tics) can have rare HDC gene mutations as a cause. The loss of histamine in the basal ganglia causes too much dopamine in that region of the brain, resulting in tics.[ref]

Too much histamine and the heart:
Histamine is also essential in the way that the heart muscle functions. Too much histamine here can be detrimental, and people with chronic heart failure have higher average plasma histamine levels. In fact, a genetic variant in the HDC gene that reduces histamine levels is linked to a significantly decreased risk of chronic heart failure.[ref] Additionally, clinical trials show that blocking the H2 receptor is beneficial for chronic heart failure. Famotidine (Pepcid AC) improved cardiac symptoms and ventricular remodeling.[ref][ref]

Histamine receptors: the differing effects of histamine

You may be wondering why one molecule can cause so many different actions in the body…

How can histamine cause headaches and heartburn and hives? 

The function of histamine in a certain part of the body depends on the receptor it binds to.

Different histamine receptors are found in different parts of the body:[ref]

  • H1 receptors: Found in smooth muscle, endothelial cells (lining the blood vessels), central nervous system, and mast cells. Activating the H1 receptors causes allergy-type symptoms such as itching, swelling, vasodilation, nose running, and skin reactions. H1 receptors are also important in asthma reactions.
  • H2 receptors: When histamine activates the H2 receptors in the stomach, acid is released. H2 receptors are also found in the intestinal tract and in the walls of blood vessels. Mast cells also have H2 receptors, which when activated, cause the release of more histamine. In the heart, H2 receptors are important in controlling the rhythm.
  • H3 receptors: The central nervous system and the peripheral nervous system contain H3 receptors, which act as a feedback loop for histamine levels in the brain. Activating the H3 receptors impacts serotonin, norepinephrine, and acetylcholine release.[ref]
  • H4 receptors: These histamine receptors are at the core of the inflammatory response. H4 receptors are found in the bone marrow, basophils (a type of white blood cell), thymus, small intestine, spleen, colon, and mast cells.[ref]

In the intestines, which is actually the body’s largest immune organ, three types of histamine receptors are found: H1, H2, and H4.  Interestingly, a study showed that people with food allergies and IBS had significantly higher levels of H1 and H2 receptors in their intestines.[ref]

Mast cells and histamine release

A type of immune cell, mast cells store histamine in most tissues in the body.

Allergens cause mast cells to burst (degranulate) and release histamine. Large numbers of mast cells are in the skin, bronchial tree mucosa, and intestinal mucosa. Mast cells are also activated by viruses, bacteria, and fungi.[ref]

Some think that histamine intolerance is a subset of mast cell activation syndrome (MCAS)

Related article: Mast cell activation syndrome

For more in-depth info on mast cells and histamine, check out Research Studies on Mast Cells and Histamine Intolerance where I dive into all the different ways histamine can affect you.

Histamine, Sleep, and Circadian Rhythm:

Histamine acts in the brain as a neurotransmitter. It is an alerting neurotransmitter, rising in the morning hours to wake us up. About 50% of the histamine in the brain is from mast cells.[ref]

Benadryl, a commonly used antihistamine, has the side effect of making people sleepy. This is due to the actions of histamine in the brain.

Altering histamine levels in the brain changes sleep:

  • In mice, knocking out the histamine receptors in the brain shows that it alters sleep patterns a little bit. Without histamine, mice were slower to wake up. They also had fragmented sleep and decreased Non-REM sleep.[ref]
  • In another animal study, researchers decreased the number of mast cells in the brain, reducing histamine production there. This did not affect the amount of time that the mice slept overall, but it did affect their brain waves in sleep as well as their ability to bounce back after sleep deprivation.[ref]

In a recent study in people who had suspected histamine intolerance, the researchers found that about 1/4 of the patients had a circadian change in histamine levels that differed from a control group.  These patients had significantly reduced DAO enzyme levels during the day and subsequently higher histamine levels.[ref]


Genetics of Histamine Intolerance:

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Breakdown of histamine:

DAO (diamine oxidase) is the enzyme produced by the intestines, breaking down histamine from foods. The AOC1 gene codes for the production of the DAO enzyme. Genetic variants in AOC1 can increase or decrease the production of the enzyme.

Note, there are rare mutations influencing DAO production not included with most genetic data, so the information below does not give you the complete picture.[ref][ref]

AOC1 gene:  encodes diamine oxidase (DAO):

Check your genetic data for rs10156191 (23andMe v4; AncestryDNA):

  • C/C: typical
  • C/T: reduced production of DAO, increased risk of migraines due to histamine[ref]
  • T/T: reduced production of DAO[ref][ref], increased risk of migraines due to histamine[ref]

Members: Your genotype for rs10156191 is .

Check your genetic data for rs2052129 (23andMe v.5 only):

  • G/G: typical (most common genotype)
  • G/T: reduced production of DAO, increased risk of migraines due to histamine[ref]
  • T/T: reduced production of DAO[ref], increased risk of migraines due to histamine[ref]

Members: Your genotype for rs2052129 is .

Check your genetic data for rs1049742 (23andMe v4 only):

  • C/C: typical
  • C/T: reduced production of DAO
  • T/T: reduced production of DAO[ref]

Members: Your genotype for rs1049742 is .

Check your genetic data for rs1049793 H645D (23andMe v4; AncestryDNA(older)):

  • C/C: typical, high
  • C/G: reduced production of DAO (35% reduction)
  • G/G: reduced production of DAO (50% reduction)[ref]

Members: Your genotype for rs1049793 is .

Check your genetic data for rs2071514 (23andMe v5; AncestryDNA):

  • A/A: possibly higher DAO[ref]
  • A/G: possibly higher DAO
  • G/G: typical

Members: Your genotype for rs2071514 is .

HNMT genetic variants:

Histamine n-methyltransferase (HMNT) is the enzyme that regulates histamine in the body via converting it from histamine into N-methylhistamine, which can then be eliminated from the body. HNMT is responsible for elimination of 80% of histamine in the body.[ref]

Check your genetic data for rs1050891 (23andMe v4, v5):

  • G/G: typical
  • A/G: reduced breakdown of histamine compared to G/G
  • A/A: reduced breakdown of histamine compared to G/G[ref]

Members: Your genotype for rs1050891 is .

Check your genetic data for rs11558538 C314T (23andMe results for i3000469, v4; AncestryDNA):

  • T/T: reduced HNMT activity[ref][ref] higher histamine
  • C/T: reduced breakdown of histamine compared to C/C
  • C/C: typical[ref]

Members: Your genotype for rs11558538 is -or- your 23andMe genotype for i3000469 is .

Check your genetic data for rs2071048 -464(23andMe v4; AncestryDNA):

  • T/T: increased risk of asthma (higher histamine), common variant[ref]
  • C/T: typical asthma risk
  • T/T: typical asthma risk

Members: Your genotype for rs2071048 is .

 

Methylation Cycle:

The methylation cycle plays a role in breaking down monoamine neurotransmitters including histamine. It is also important in creating the methyl groups needed for the HMNT enzyme to work. So looking at your methylation cycle genes can also help with balancing out a histamine intolerance.

The MTHFR gene codes for an enzyme that is a key player in the folate cycle. This is one source of methyl groups for the methylation cycle. Decreased enzyme activity of MTHFR – combined with a diet lacking in folate or choline – may cause a reduced breakdown of histamine.

Check your genetic data for rs1801133 (23andMe v4, v5; AncestryDNA):

  • G/G: typical
  • A/G: one copy of MTHFR C677T allele (heterozygous), decreased enzyme function by 40%
  • A/A: two copies of MTHFR C677T (homozygous), decreased enzyme function by 70 – 80%

Members: Your genotype for rs1801133 is .

Check your genetic data for rs1801131 (23andMe v4, v5; AncestryDNA):

  • T/T: typical
  • G/T: one copy of MTHFR A1298C (heterozygous), slightly decreased enzyme
  • G/G: two copies of MTHFR A1298C (homozygous), decreased enzyme by about 20%

Members: Your genotype for rs1801131 is .

Creation of Histamine:

HDC gene: encodes the histidine decarboxylase enzyme which is used in the conversion of histidine into histamine

Check your genetic data for rs2073440 (23andMe v4, v5; AncestryDNA):

  • T/T: typical
  • G/T: Decreased risk of allergic rhinitis (less histamine)
  • G/G: Decreased risk of allergic rhinitis (less histamine)[ref]

Members: Your genotype for rs2073440 is .

Check your genetic data for rs2073440 (23andMe v4, v5; AncestryDNA):

  • G/G: reduced HDC, reduced risk of chronic heart failure[ref]
  • G/T: reduced HDC, reduced risk of chronic heart failure
  • T/T: typical

Members: Your genotype for rs2073440 is .

Check your genetic data for rs267606861 (AncestryDNA only):

  • C/C: typical
  • A/C: carrier of a pathogenic mutation for Tourettes, reduced HDC (rare) [ref]

Members: Your genotype for rs267606861 is .

Histamine Receptors:

HRH1 gene: histamine receptor 1

Check your genetic data for rs901865 (23andMe v4, v5; AncestryDNA):

  • C/C: typical
  • C/T: increased asthma risk (likely increased HRH1)
  • T/T: increased asthma risk (likely increase HRH1)[ref]

Members: Your genotype for rs901865 is .

HRH2 gene: histamine receptor 2

Check your genetic data for rs2067474 (23andMe v4, v5; AncestryDNA):

  • A/A: Decreased HRH2; protective against chronic heart failure[ref],
  • protective against gastric cancer[ref], lower risk of gastritis[ref]
  • A/G: protective against chronic heart failure, protective against gastric cancer, lower risk of gastritis
  • G/G: typical (more common genotype) higher HRH2, higher risk of CHF, gastritis

Members: Your genotype for rs2067474 is .

HRH4 gene: histamine receptor 4

Check your genetic data for rs11662595 (23andMe v4, v5; AncestryDNA):

  • A/A: typical
  • A/G: decreased HRH4 activation (receptor dysfunction), increased risk of progression in non-small cell lung cancer
  • G/G: decreased HRH4 activation (receptor dysfunction), increased risk of progression in non-small cell lung cancer[ref]

Members: Your genotype for rs11662595 is .

 


Lifehacks for histamine intolerance

Below are the research-backed solutions for histamine intolerance. You may need to try several different ‘lifehacks’ to see which works best for you.

A Low-histamine diet, at least initially:

A low-histamine diet restricts foods that contain high levels of histamine or that cause the body to release histamine. To experiment with a low-histamine diet, eliminate all of the higher histamine foods for a period of time to see how your body responds.

While there are many partial lists for low-histamine diets, I find this list to be the most thorough:  A complete list of foods that are high in histamine 

What does a low-histamine diet do?

  • Decreasing the amount of histamine that you take into your body will lower the overall amount circulating in your body.
  • Research studies show that a low histamine diet helps chronic urticaria (itchiness, hives), migraines, stomach problems, and asthma.[ref][ref]

Should you maintain a low histamine diet long-term?

Trying a low-histamine diet for a period of time can give you a lot of insight into how histamine is affecting your body, but it may not be a diet that you want to continue long-term. A low-histamine diet restricts a lot of ‘healthy’ foods that you may enjoy, such as spinach, strawberries, and avocados.

Use it as a tool to learn which histamine-containing foods bother you the most and as a short-term way of getting histamine responses under control.

Low FODMAPs diet: histamine and gut problems

Interestingly, a randomized controlled study for people diagnosed with IBS found that a low FODMAPs diet reduced symptoms as well as reducing histamine. This could mean that a FODMAPs diet works because IBS is related to histamine intolerance – or – could mean that the people diagnosed with IBS were really dealing with gut-related histamine symptoms.[ref]

A low FODMAPs diet cuts out a lot of high histamine foods, so it could be reducing histamine levels through eating fewer foods high in histamine. On the other hand, a low FODMAPs diet is impacting the gut microbiome and histamine producing bacteria.

Learn more about what is included in a low FODMAPs diet: Starting a Low FODMAPs diet

Vitamins & Natural Supplements for Histamine Intolerance:

Vitamin B6 is a cofactor in the reactions that degrade histamine. Pyridoxal-5′-phosphate is the active form of vitamin B6. Foods high in vitamin B6 include salmon, tuna, eggs, milk, beef, and carrots.(article)  Not sure if you get enough vitamin B6? Cronometer.com is a free online app where you can record the foods you eat each day to determine the nutrient content – and it includes the vitamin B6 content of foods.

Quercetin has also been shown in studies to inhibit mast cells from degranulating. Mast cells are one way that the body releases histamine.[ref]

Fisetin, another natural flavonol, has been shown in cell studies to inhibit mast cells from degranulating.[ref][ref][ref](Read more about fisetin)

Luteolin has been shown in studies to inhibit histamine release from mast cells.[ref]

There are DAO supplements available that may help some people who don’t produce enough of the enzyme. A recent study found that histamine intolerance symptoms improved significantly when taking DAO capsules before meals.[ref]

Looking for an alternative to expensive DAO supplements? Pea shoots – those first few inches of the pea plant that come up in the spring –  are naturally high in the DAO enzyme.[ref] You can easily grow pea shoots at home, and they are a tasty addition to a salad.

Gluten sensitivity and histamine intolerance

A new study looked at the correlation between symptoms of histamine intolerance and gluten intolerance.  It concluded that there was a significant overlap in symptoms and that it is possible that a low histamine diet may help people with gluten sensitivity.[ref]

Food preparation methods to reduce histamine levels

How food is prepared makes a big difference in the histamine levels.

A recent study concluded “Frying and grilling increased histamine levels in foods, whereas boiling had little influence or even decreased it. The boiling method might be helpful to control the effect of histamine in histamine-sensitive or susceptible patients, compared with frying and grilling.”

Additionally, leftovers kept in the fridge (especially meats!) can build up histamine. Instead, try putting your leftovers in the freezer and thawing them when you want to eat them.

As you will see on the list of foods high in histamine, fermenting and drying foods can increase histamine levels.

Avoid medications that decrease DAO enzyme production

In addition to foods, drug interactions can cause a decrease in DAO enzyme production.

  • Metformin has been shown to decrease the DAO enzyme.[ref]
  • Vitamin B3 (nicotinamide or niacinamide) may increase histamine levels at doses of 100 mg or higher.[ref]

Extras for Members:

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Related Articles and Topics:

Mast cells: MCAS, genetics, and solutions
Mast Cell Activation Syndrome, or MCAS, is a recently recognized disease involving mast cells that misbehave in various ways. Symptoms of MCAS can include abdominal pain, nausea, itching, flushing, hives, headaches, heart palpitations, anxiety, brain fog, and anaphylaxis. Dive into the research on mast cells, genetics, and solutions.

Notes about Histamine and Mast Cells
A compilation of notes and reference studies on the functioning of mast cells and histamine receptors.

Tyramine: The Cheese Effect and Your Genes
Tyramine is another biogenic amine, found in a lot of the same foods as histamine. An inability to break down tyramine can cause a variety of symptoms.

Top 10 Genes to Check in Your Genetic Raw Data
Wondering what is actually important in your genetic data? These 10 genes have important variants with a big impact on health. Check your genes (free article).

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Originally published April, 2015. 

 




Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.