Is Histamine Intolerance Genetic? DAO, HNMT, MTHFR and Other Important Genes
Is histamine intolerance in your genes?
Your genes dictate who you are, and this is true for what happens both from a physical and a biological perspective!
Think about your eye and hair color. You weren’t randomly assigned to be born with green eyes and blonde hair, for example.
Your carefully constructed genetic code allocated those specific traits to you, long before you were even conceived.
In terms of biological genes, they are also responsible for your body shape, your likes and dislikes, your personality, and a whole lot of other things about you that make you, you.
Genes are also in control of many aspects of your health. Our genes can provide us with either protective aspects against certain diseases and conditions, or they can leave us more at risk.
When it comes to histamine intolerance (HIT), there are a number of genes that have been found to increase the risk of developing this condition.
Common genes that affect histamine intolerance: DAO, HNMT, MTHFR, MAO and HDC
Without getting into too much of the science behind genes, there’s a little bit about them you need to know to understand why a genetic factor can be the cause of your symptoms of HIT.
Each gene is made up of a number of different codes. These codes tell the body to use specific nutrients to make enzymes.
Enzymes are what make the entire body functions as it should, where these little compounds tell each cell what it needs to do.
Some genes have been put together with the wrong code, where it’s possible that a ‘typo’ crept in when your DNA was being made, or, you inherited the typo from one of your parents.
Depending on how much of the code is wrong, the capacity of the enzyme which it instructs will be reduced, and so the enzyme simply doesn’t work at 100% of its true efficiency.
There are five common genetic changes that can increase your risk of histamine toxicity.
1. DAO - AOC1
Diamine oxidase (DAO) is an enzyme that the body uses to break down histamine. When there is too little of this enzyme produced, histamine levels within your system increase.
DAO is the primary enzyme that you need for histamine to break down, particularly when it comes to histamine in the gut. Because there is a chance of high histamine influx into the digestive system, both from food and that which is produced by gut bacteria, DAO really needs to be on point. When it’s not, and the gene that codes for its production is not working effectively, symptoms of histamine intolerance can arise(1,2).
When it’s a DAO deficiency that’s the cause of histamine intolerance, it’s referred to as a primary DAO insufficiency.
DAO supplements are available, which work very well when it comes to helping to break down histamine in the gut. The supplements, however, don’t add to the body’s overall capacity to produce DAO, making them a symptom-relieving option rather than being able to fix the root cause.
2. HNMT - C939T
Another enzyme the body uses to break down intracellular histamine that is made or released elsewhere in the body is called histamine N-methyltransferase (HNMT). It is particularly active in the central nervous system, which is made up of the brain and the spinal cord(3). When there is insufficient HNMT made due to a genetic predisposition, there may be an increase in the symptoms of histamine intolerance associated with activation of the receptors in the brain, such as heightened anxiety, mood swings, and even Parkinson’s Disease(4,5,6).
3. MAO - MAO
Monoamine oxidase (MAO) is yet another enzyme that helps to degrade biogenic amines such as tyramine, histamine and catecholamines. While it’s not the primary function of MAO to degrade histamine, too little of this enzyme can still impact histamine levels. Symptoms may be even more severe when there is a change in the gene that dictates the production of MAO, as levels of the other biogenic amines rise, too(7).
4. MTHFR - A1298
It is believed that around 50% of people have the MTHFR genetic mutation. This enzyme, called methylenetetrahydrofolate reductase (MTHFR), is an important one involved in the folic acid cycle. It’s a critical step in converting folic acid into another essential compound that is needed for a process called methylation.
Methylation is one of the pathways the body uses for detoxification, energy production, repair and inflammatory responses, and it also helps to reduce the body’s histamine levels. Methylation status can seriously impact histamine levels, where a decrease in the ability to methylate with this gene mutation can cause mast cells to release more histamine into the body(8,9).
There is a way to skirt around this gene and its impact on methylation. Taking a methylated folic acid supplement for example, or increasing your choline intake, can help to improve methylation capacity and influence the processes needed for histamine balance(10,11,12).
5. Histidine decarboxylase - HDC
Histidine decarboxylase (HDC) dictates how easily the body can make histamine from the ingested amino acid histidine. When there is a mutation in this gene, histamine levels may rise. Research shows that those who have changes in this gene are more prone to developing allergies and a runny nose as a result(13,14).
Histamine intolerance and genetics: the bottom line
What is important to realize is that, while you may be a carrier of some of these genes, they don’t always mean for certainty that a condition will develop.
The ‘activation’ of a specific gene can cause symptoms to develop, however, should these factors that influence the gene be managed, and the triggers of that gene be moderated, the condition may be well managed.
This concept is certainly applicable to histamine intolerance.
Even if you have a reduced capacity to produce DAO because of a genetic predisposition, for example, decreasing your intake of foods that further inhibit DAO production may help to improve symptoms of HIT.
Supporting the body and its genetic processes can be the reason you are able to fully manage your condition with few, or no symptoms related to it.
For this reason, a histamine reduced diet is one of the best ways to quickly decrease the symptoms of histamine intolerance as it significantly reduces the load that histamine may be having on your body. For a detailed list of foods to eat and avoid, as well as more information on relieving histamine intolerance symptoms, click below to get my free eBook which is the ultimate guide to histamine intolerance!
Petersen J, Raithel M, Schwelberger HG. Characterisation of functional polymorphisms of the human diamine oxidase gene. Inflamm Res 2005;54(suppl):S58–9. https://www.ncbi.nlm.nih.gov/pubmed/15928835
Maintz, L. et al. (2011). Association of single nucleotide polymorphisms in the diamine oxidase gene with diamine oxidase serum activities. Allergy, 66(7), 893-902. https://www.ncbi.nlm.nih.gov/pubmed/21488903
Schwartz, J , et al. Histaminergic transmission in the mammalian brain. 1991. Physiol. Rev. , 71, 1–51. https://www.physiology.org/doi/full/10.1152/physrev.19126.96.36.199?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed
Heidari, A., et al. Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability. 2015. Human Molecular Genetics. 24(20):5697-5710. https://academic.oup.com/hmg/article/24/20/5697/556613
Jiménez-Jiménez, F., et al. Thr105Ile (rs11558538) polymorphism in the histamine N-methyltransferase (HNMT) gene and risk for Parkinson disease. A PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore). 2016 Jul; 95(27): e4147. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058861/
Agúndez, J., et al. Nonsynonymous polymorphisms of histamine-metabolising enzymes in patients with Parkinson's disease. Neuromolecular Med. 2008;10(1):10-6. Epub 2007 Nov 6. https://www.ncbi.nlm.nih.gov/pubmed/17985251/
Maršavelski, A., & Vianello, R. What a Difference a Methyl Group Makes: The Selectivity of Monoamine Oxidase B Towards Histamine and N‐Methylhistamine. 2017. Chemistry: A European Journal. 23(12). https://onlinelibrary.wiley.com/doi/abs/10.1002/chem.201605430
Haenisch, B., Nöthen, M. M., & Molderings, G. J. (2012). Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics. Immunology, 137(3), 197–205. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2567.2012.03627.x
Fryar-Williams, S. Fundamental Role of Methylenetetrahydrofolate Reductase 677 C → T Genotype and Flavin Compounds in Biochemical Phenotypes for Schizophrenia and Schizoaffective Psychosis. 2016. Front. Psychiatry. https://www.frontiersin.org/articles/10.3389/fpsyt.2016.00172/full#B60
Chmurzynska, A., et al. Associations between folate and choline intake, homocysteine metabolism, and genetic polymorphism of MTHFR, BHMT and PEMT in healthy pregnant Polish women. Nutrition & Dietetics. 2019. https://onlinelibrary.wiley.com/doi/abs/10.1111/1747-0080.12549
Chew, T., et al. Folate Intake, Mthfr Genotype, and Sex Modulate Choline Metabolism in Mice. 2011. The Journal of Nutrition. 141(8): 1475-1481. https://academic.oup.com/jn/article/141/8/1475/4630515
Shin, W., et al. Choline Intake Exceeding Current Dietary Recommendations Preserves Markers of Cellular Methylation in a Genetic Subgroup of Folate-Compromised Men. J Nutr. 2010 May; 140(5): 975–980. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855263/
Garcia-Martin, E., et al., Histamine pharmacogenomics. Pharmacogenomics, 2009. 10(5): 867-83. https://www.ncbi.nlm.nih.gov/pubmed/19450133
Gervasini, G., et al., Variability of the L-Histidine decarboxylase gene in allergic rhinitis. 2010. Allergy. 65(12): p. 1576-84. https://www.ncbi.nlm.nih.gov/pubmed/20608921