High Histamine, MTHFR, and the Methylation Cycle

Histamine is a molecule that plays many roles in the body. It is involved in allergic reactions, plays a role in our immune defense system, acts as a vasodilator, and is a neurotransmitter.  While most of us think of histamine only when reaching for an anti-histamine during allergy season, it is a vital part of our body’s everyday functions.

Histamine that is out of balance with the body’s ability to break it down can cause symptoms collectively known as histamine intolerance. Histamine intolerance symptoms include headaches, migraines, anxiety/irritability, acid reflux, nausea, arrhythmia, sinus drainage, and more.

Genetics plays a role in how well your body breaks down histamine.  Read on to find out how to check your genetic data for genes involved with histamine levels.

What is histamine intolerance?

The leading causes of histamine intolerance are too few enzymes needed to break down histamine and/or too much histamine production. (gut microbes or mast cells). This article digs into the genes involved in the production of the enzymes that break down histamine.

Histamine is broken down and excreted by the diamine oxidase (DAO) enzyme in the gut and the histamine methyltransferase (HMNT) enzyme throughout the body.

Related Article: How your genes increase the risk of histamine intolerance

Histamine and the methylation cycle:

The HNMT enzyme is found throughout the body. This enzyme works to add a methyl group to histamine. The methylated histamine molecules can then be excreted easily in the urine.[ref]

Methyl groups are simply a carbon with three hydrogens. SAMe (s-adenosyl-L-methionine) is the primary donor of methyl groups, and SAMe production relies on the body having enough folate, vitamin B12, and choline available to produce methyl groups.[ref]

Some people have genetic variants that negatively impact the methylation cycle, but fortunately, it is modifiable with a diet high in folate and choline.

Genetics of Histamine Intolerance:

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Genetic variants of the AOC1/ABP1 gene can affect DAO enzyme production, and HMNT variants can also cause variations in the production of that enzyme. Some of the variants included with 23andMe results are listed below. Note that there are rarer mutations that influence DAO production not included with 23andMe data, so the information below may not give you the complete picture.[ref][ref]

AOC1/ABP1 Gene:

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

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

Members: Your genotype for rs10156191 is .

Check your genetic data for  rs2052129 (23andMe v5):

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

Members: Your genotype for rs2052129 is .

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

  • C/C: typical
  • C/T: reduced production of DAO
  • T/T: reduced production of DAO

Members: Your genotype for rs1049742 is .

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

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

Members: Your genotype for rs1049793 is .

HNMT Gene:

Histamine n-methyltransferase is an enzyme that regulates histamine through metabolizing it from histamine to N-methylhistamine.

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][ref]

Members: Your genotype for rs1050891 is .

Check your genetic data for rs11558538 (23andMe v4 i3000469; AncestryDNA- rs11558538):

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

Members: Your genotype for i3000469 is .

Methylation Cycle:

The methylation cycle plays a role in breaking down monoamine neurotransmitters, including histamine.  So looking at your methylation cycle genes can also help with balancing out a histamine intolerance.

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

  • G/G: typical *
  • A/G: one copy of MTHFR C677T allele, enzyme function decreased by 40%
  • A/A: two copies of MTHFR C677T, enzyme function decreased 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 function
  • G/G: two copies of MTHFR A1298C (homozygous), decreased enzyme by about 20%

Members: Your genotype for rs1801131 is .


Related Articles: MTHFR: How to check your data for C677T and A1298C and MTR / MTRR – Homocysteine, methionine, and B12.


Most people with histamine intolerance find that a low histamine diet can help manage symptoms while getting to the root cause. There are many lists online for foods that are high in histamine or cause the release of histamine. Here is the list that I like to use.

How can you lower histamine levels?

A low histamine diet can be difficult to incorporate at first, but it should only take a few days to a week to know if it is helping your histamine intolerance type symptoms.  Several research studies show that a low histamine diet helps with chronic urticaria (itchiness, hives), migraines, and asthma.[ref][ref]

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 a low histamine diet may help people with gluten sensitivity.[ref]

Food preparation makes a difference in histamine levels. A recent study concluded, “Frying and grilling increased histamine level 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.”

Can medications affect histamine levels?

In addition to foods, drug interactions can cause a decrease in DAO enzyme production. Metformin decreases the DAO enzyme.[ref]

For anyone taking nicotinamide (also called niacinamide or B3), this interesting research paper looks at increased plasma histamine levels after taking 100 mg of nicotinamide.

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.