Histamine Intolerance - The genes and pathways of breaking down histamine.

Histamine Intolerance – The genes and pathways of breaking down histamine.

Are you itching by the end of the day?  Miserable in the evening due to heartburn?  Nose constantly stuffy and drippy? Plagued by migraines? All of these (and more) can be related to histamine intolerance. (Update to this article is here.)

First, symptoms of histamine issues can be more than just watery eyes and sneezing when the pollen count rises each spring.

From The American Journal of Clinical Nutrition:

[Histamine] causes smooth muscle cell contraction, vasodilatation, increased vascular permeability and mucus secretion, tachycardia, alterations of blood pressure, and arrhythmias, and it stimulates gastric acid secretion and nociceptive nerve fibers. In addition, histamine has been known to play various roles in neurotransmission, immunomodulation, hematopoiesis, wound healing, day-night rhythm…

Symptoms of histamine intolerance can include:

  • headaches
  • migraines
  • dark circles under the eyes
  • itching, hives
  • congestion, sneezing, runny nose
  • acid reflux
  • anxiety, irritability, hyperactivity
  • digestive issues
  • tachycardia or arrhythmia
  • fatigue

I like the way the author of Peeling Back the Onion Layers explains it:

Everyone has a different tolerance for histamines. Some have serious mast cell disorders and need to be extremely vigilant about histamines in the diet. Some people need to restrict histamines in their diet to avoid migraines and terrible insomnia. Others just need to watch their histamine load to avoid crossing their threshold and feeling a little cranky or noticing a decline in their digestion.

A lack of the diamine oxidase (DAO) enzyme can cause issues with histamines.  The gene AOC1 codes for the production of diamine oxidase.  There are a couple of AOC1 polymorphisms included in 23andMe data that have been linked to reduced production of DAO.

Check your 23andMe results for rs10156191:

  •  CC: Normal DAO production
  •  CT: Reduced DAO production [ref]
  •  TT: Reduced DAO production


Check your 23andMe results for rs1049742:

  •  CC: Normal DAO production
  •  CT: Reduced DAO production [ref]
  •  TT: Reduced DAO production


So how does this tie together with the methylation cycle?  From Chapter 2: Nutrigenomics and the Methylation Cycle by Dr. Amy Yasko:

The functional areas impacted by improper methylation are in a dynamic relationship with one another—that is, they are mutually interactive. So it is with the relationship of your immune cells to digestive issues. Since many of your immune cells reside in the digestive tract, there’s a close relationship between methylation, immunity, and such digestive problems as leaky gut, allergies, and various forms of digestive distress that the children commonly experience. Briefly, if methylation is low and T cell production is low, then histamine levels tend to be high. Histamine is linked to inflammation, a contributing factors to leaky gut as well as allergies.

With the underactivity of T cells, B cell activity can take over, which can lead to autoimmune issues like allergies and food sensitivities.

This makes sense when you look at the big picture of how methylation cycle problems can affect the health of the whole body.  I do need to note, though, that this is not something for which I can find any research studies to back up Dr. Yasko’s position.

So for those who have MTHFR polymorphisms or other methylation cycle problems, histamine intolerance can be tied into overall immune health.   As your health overall improves, often histamines will become less of a problem.

A diet of low histamine foods can help to get you back on track and manage the symptoms that too much histamine is causing you.  But getting to the root of the matter will require a healthy gut.  For those with methylation cycle issues, a diet rich in green vegetables will help increase folate levels, and there are supplements for methylfolate and B12 that may help as well.* Another avenue to look at for gut health and inflammation is the role that surfactants in our foods play in our gut microbiome.

Additional Reading:


Histamine Intolerance & Genetics: Check Your 23andMe Raw Data


Updated Feb. 2017


Sharon K Smith · June 13, 2018 at 10:16 pm

The information that I’ve gotten on both 23and me and genetic life hacks has illuminated why I got so sick in my late 30’s. I was suffering from histamine overload from mold allergies, and since I have the MTHFR 40% folate reduction and the DAO enzyme issue, it all seems so clear now. I appreciate the work you folks have done!

    Debbie Moon · June 14, 2018 at 7:04 am

    Hi Sharon – Thanks so much for your comments! I hope this helps you to get your histamine issues worked out. I’ve traveled down a similar road; it is worthwhile to get to the bottom of the problem and no longer deal with nagging symptoms.

Melanie · December 30, 2018 at 2:41 am

I uploaded my 23andme data, but unfortunately they skipped testing a bunch of stuff and none of the histamine rsids were shown. This makes so much sense, though! I tend to become VERY itchy at night sometimes, and other times not so much. Thank you for the information!

    Debbie Moon · December 30, 2018 at 1:11 pm

    Hi Melanie,
    Yes – it is unfortunate that the newer version of 23andMe (v5) doesn’t cover the genetic variants associated with histamine intolerance very well. I have another article on histamine intolerance that does include a few variants that are included in the v5 data: https://www.geneticlifehacks.com/histamine-intolerance-genetics-part-2/
    Hope this helps! Give a low histamine diet a try for a week or so and see if the itching at night goes away :-)

Genetic Lifehacks | Low Histamine Smoothie Bowl · April 8, 2015 at 9:31 pm

[…] to eat a low histamine diet can quickly become boring!  Here is a recipe for a smoothie bowl that I like as quick […]

Genetic Lifehacks | Histamine Intolerance & Genetics, Part 2 · July 21, 2015 at 10:42 am

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

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