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 that are 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…

Histamine Intolerance:
The main causes of histamine intolerance are too little of the enzymes that are needed to break down histamine, and/or too much histamine being produced (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.


Genetics of Histamine Intolerance:
Genetic variants of the AOC1/ABP1 gene can affect how much DAO enzyme is produced, and HMNT variants can cause variations in the production of that enzyme also. Some of the variants that are 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 Gene:

Check your23andMe results for rs10156191 (v.4 only):

  • CC: normal
  • CT: reduced production of DAO
  • TT: reduced production of DAO[ref]

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

  • GG: normal
  • GT: reduced production of DAO
  • TT: reduced production of DAO [ref]

Check your 23andMe results for rs1049742 (v.4 only):

  • CC: normal
  • CT: reduced production of DAO
  • TT: reduced production of DAO

Check your 23andMe results for rs1049793 (v.4 only):

  • CC: normal
  • CG: reduced production of DAO
  • GG: reduced production of DAO [ref]

 

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

Check your 23andMe results for rs1050891 (v.4 and v.5):

  • AG: reduced breakdown of histamine compared to GG
  • AA: reduced breakdown of histamine compared to GG [ref]

Check your 23andMe results for i3000469 (v.4 , rs11558538):

  • TT: reduced breakdown of histamine
  • CT: reduced breakdown of histamine compared to CC
  • CC: normal [ref]

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.


Lifehacks

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.

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.  There are several research studies showing that a low histamine diet helps chronic urticaria (itchiness, hives), migraines, and asthma. [ref][ref]

There are DAO supplements available that may help some people who don’t produce enough of the enzyme. Additionally, pea shoots are supposed to be naturally high in DAO.[ref] You can easily grow pea shoots at home!

Quercetin has also been shown in studies to inhibit mast cells from degrading and increasing histamine levels.[ref]

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

How food is prepared makes a difference in the 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.”

In addition to foods, drug interactions can cause a decrease in the DAO enzyme production. Metformin has been shown to decrease the DAO enzyme.

For anyone taking nicotinamide (also called niacinamide or B3), here is an interesting research paper looking at the increase in plasma histamine level after taking 100 mg of nicotinamide.

 


More background information:

Histamine Receptors:
The other side of the histamine equation is the histamine receptors to which histamine binds.

  • H1: smooth muscle, endothelium (cells lining the inside of blood vessels and lymph vessels), central nervous system tissue, mast cells   (discovered in 1966)
  • H2: Gastrointestinal, vascular smooth muscle tissue (walls of blood vessels), mast cells  H2 receptors are blocked by Tagamet. (discovered in 1972)  “H2 receptors mediate histamine stimulation of gastric acid secretion and may be involved in cardiac stimulation”
  • H3: Central nervous system and some peripheral nervous system, mast cells (discovered in 1987)   “feedback inhibitors in CNS”
  • H4: Bone marrow, basophils (a type of white blood cell), thymus, small intestine, spleen, colon, mast cells  (discovered in 2001) “considered to have a role in a number of inflammatory disorders such as allergy, asthma, chronic pruritus and autoimmune diseases” [ref]

In the intestines, which is the body’s largest immune organ, three types of histamine receptors have been found: H1, H2, and H4. Low levels of H3 were found in intestinal samples in a few of the study participants. Interestingly, those with food allergies and IBS had significantly higher levels of H1 and H2 receptors in their intestines.  [ref]

Mast Cells:
Mast cells are the storage site for histamine in most tissue. 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. Some think that histamine intolerance is a subset of MCAS (mast cell activation syndrome).

Read even more: Notes about Histamine and Mast Cells

 

Updated 2/2018

 


22 Comments

lc · March 31, 2016 at 2:00 pm

If 23 and me does not contain all the polymorphisms of DAO production or all the mutations of HNMT related to histamine breakdown, what series of additional tests can you recommend that would help me get to the bottom of my sky high histamine levels and mast cell activation diagnosis? My doctor mentioned getting testing like this, but I want to get THE MOST comprehensive set of testing done that I can, and it sounds like 23 and me is missing many things.

Marco · July 7, 2016 at 3:19 pm

MTHFRsupport.com calls C the Risk Allele for both rs1049793 (ABP1/DAO H664A) and rs10156191 (ABP1/DAO T16M).

This seems to be in conflict of what you wrote. Can you please double check :)

Thanks.

    genelife · July 7, 2016 at 4:41 pm

    Thanks so much for letting me know that MTHFRsupport has a difference for their risk allele. I did a quick check of dbSNP and I do believe that I have the risk alleles listed correctly as the minor alleles for those snps. I will go back through my references, though, and double check all of them to make sure that the minor (less common) allele is the one causing a decrease in DAO for both snps. Otherwise, I am not sure where MTHFRsupport got their information, so I can’t say why they would have the major (more common) allele as the risk allele. New studies are coming out all the time, so it is a good reminder for me to see if there is anything new for DAO enzyme snps!

    Grace · July 18, 2017 at 7:59 pm

    The minor allele for rs10156191 is associated with increased risk for reduced DAO activity according to this article:
    https://www.ncbi.nlm.nih.gov/pubmed/?term=dao+variants+histamine+intolerance

Matt · February 28, 2017 at 8:09 am

This is my 23andme data:

HNMT rs1050891 138771760 A or G A / A

But you wrote about C’s and T’s for rs1050891. Super confused

    Matt · February 28, 2017 at 8:14 am

    Ok nevermind, I see the link for “Check your 23andMe results for i300469:” links to “rs1050891” (guessing its a typo?). Hence why I was confused.

    Also, my 23andme data (v3 chip) has nothing for either rs11558538 or i300469

Matthew F. Reyes · May 1, 2017 at 5:21 pm

Greetings.
A few questions here.

Firstly, your first note with a link to 23andMe for ABP1:
23andMe results for rs10156191:

has two URLs embedded into. One seems correct,
https://you.23andme.com/tools/data/?snp_name=rs10156191
the other is for an intergenic region that I’m not seeing the connection to.
https://you.23andme.com/tools/data/?snp_name=rs366631

Secondly, your last note regarding HMNT is also in error,

Check your 23andMe results for i300469:
perhaps a copy/paste glitch as it’s a duplicate of an earlier link

Now, last point of confusion which isn’t your fault: you cannot search 23andMe for i300469. Not sure why, but the best way to dig this marker up is to go straight to the HMNT gene page and scroll down until you find it.

https://you.23andme.com/tools/data/?gene_name=HNMT

Hope this helps.

    genelife · October 30, 2017 at 2:38 pm

    Thanks so much for your comments on the HMNT page. Sorry that it has taken me so long to post a reply – somehow your comment was flagged as spam, which I’m just now cleaning out! I really appreciate your comments on the links and the link to the research study and will check into them and get them updated ASAP.

Matthew F. Reyes · May 2, 2017 at 1:01 am

I also need a small bit of handholding here. The reference you provided for rs1050891 links to a paper on the Theoretical 3D structure of HNMT:

https://www.ncbi.nlm.nih.gov/pubmed/11549275

However, the paper makes reference to a Thr105Ile polymorphism that references the rs11558538 SNP (aka i300469 in 23andMe)..

Moreover, the SNP rs1050891 is located in the intron region of XR_001739719.1.

Can you please double check what references you’re citing for these particular claims?

D · June 27, 2017 at 12:19 am

What about DAO rs3741775? that has no clinical reference to histamine?

    genelife · June 27, 2017 at 7:06 am

    Hi –
    I don’t know that it does have anything to do with histamine. The DAO gene codes for d-amino acid oxidase. It looks like they have done a lot of studies on that polymorphism in regards to schizophrenia: https://www.snpedia.com/index.php/Rs3741775
    Thanks for the comment.
    Debbie

Grace · July 18, 2017 at 7:41 pm

The HNMT SNP should say: i3000469.

    genelife · July 19, 2017 at 2:51 pm

    Thanks for catching the missing “0” in that i number! Appreciate you reading the blog and commenting.
    Debbie

      Grace · July 19, 2017 at 3:33 pm

      Thank you for your website, Debbie! It helped me quickly identify some variants for histamine intolerance. You did a lot of work that I was planning on doing, so thank you for sharing!

Brandy Chappell · September 23, 2017 at 12:00 pm

Excellent and easy to understand article which gets to the point. So many other blogs just jump from topic to topic you made this very easy to cover all the issues in one succinct shot. Thanks!

    genelife · September 23, 2017 at 6:20 pm

    Thanks so much! Glad you are able to get something out of the blog post.

Melissa Wicklund · October 23, 2017 at 9:03 pm

Hello, what if I checked my 23andme for all of these and only had abnormalities with rs1049793 (I had c/g) and with rs1050891 (I had A/A) allof the other ones on the list that you said to check came back normal…..would these two suggest a histamine intolerance??? I am trying to get to the bottom of my 13 year long suffering with migraines. Nothing has ever worked before except 5 days ago I started taking Tumeric on the medical advice of a nurse and it worked!! When I looked up why Tumeric works it stated that it generally works on histamine migraines. I have been tested for all kinds of outside allergies and I have none. Although, I am very allergic to dairy. Any insight would be very helpful!!

    genelife · October 24, 2017 at 11:10 am

    The DAO variant (rs1049793) is just going to give you a minor decrease in breaking down histamine in the gut and probably isn’t enough to give you histamine problems on its own. The HMNT variant (rs1050891) is what inactivates histamine in the body, so being slower on that enzyme can come into play with not being able to tolerate as much histamine. So while you have some genetic susceptibility to not tolerating a lot of histamine, it may or may not be the problem for your migraines.
    One way to tell is to simply try a low histamine diet for a couple of weeks. For me, a low histamine diet was the key for migraines, heartburn, and sinus drainage. After a few months of a low histamine diet, I was able to kind of dial it in and figure out what foods were the worst for me. I had previously been eating a lot of fermented foods and long-cooked bone broth, plus was taking probiotics that were histamine producing. So while genetics was playing a role for me in being unable to metabolize histamine as well as some people can, I think my histamine problems really came from my gut microbiome. I would say that I now can eat anything — but in reality, I have just gotten good at balancing out my diet and the way that I cook so that I don’t eat a lot of high histamine foods at any one meal.

Alexander Hawkins · May 6, 2018 at 5:06 am

As an fyi, I just received my results from 23andme and I can attest that the company no longer genotypes the following: rs10156191, rs366631, rs1049742, rs1049793, or i3000469. It’s a shame.. as I was hoping to get more information about my histamine processing, but it looks like I will have to purchase another company’s services for that.

    Gd · May 18, 2018 at 3:25 pm

    I have 23andme and found all except rs2052129. I have 5 people in the system and found rs10156191, rs1049742, rs1049793, and i3000469 for everyone via the “Your Raw Data” page. fyi

Genetic Lifehacks | PMS, Genetics, and Solutions · May 21, 2015 at 2:38 pm

[…] especially for menstrual cramps.  You can read up on the genes involved in histamine intolerance here and here – as well as Googling histamine intolerance.   Perhaps a diet lower in histamines […]

Histamine Intolerance & Genetics, Part 2 | ... · May 22, 2015 at 8:43 pm

[…] Please read through part 1 for more background on Histamine Intolerance. For another, excellent overview of histamine intolerance, visit the PaleoMom site: Histamine Intolerance. Causes of Histami…  […]

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