November 09, 2014 9:00 pm


A new study by Maintz and Novak et al. concludes that the histamine intolerance and diamine oxidase connection alone does not explain histamine intolerance.

Previously, genetic mutations in diamine oxidase were hypothesized to be the sole cause.

Histamine Intolerance

Histamine intolerance results from an imbalance between histamine and the capacity for histamine degradation.

There are two primary enzymes responsible for this degradation: diamine oxidase (DAO), which regulates histamine extra-cellularly, and Histamine-N-methyltransferase (HNMT), which regulates histamine intra-cellularly. When one or both of these enzymes are defective, histamine accumulates in the body.


Genetic Study

Maintz and Novak studied 285 patients with histamine intolerance and 199 healthy individuals to evaluate whether DAO gene variants (SNPs) could explain histamine intolerance. Furthermore, they tried to determine whether these SNPs were associated with decreased or increased DAO activity.

Here are the significant results:


Reduced DAO

DAO activity is highly variable amongst the general population.

Patients with histamine intolerance are more likely to have reduced levels of diamine oxidase activity (50% of patients with histamine intolerance versus 17% of healthy controls), and those with reduced levels of DAO are more likely to have symptoms of histamine intolerance.

However, this was not an absolute correlation as not everyone with histamine intolerance had reduced levels of DAO activity.


histamine intolerance, genetics, diamine oxidase, DAO, Alison Vickery, Health, Australia

Genetic Mutations

The study found that 5 SNPs were significantly associated with DAO activity.

Four of them: rs2052129, rs2268999, rs10156191, and rs1049742, are associated with a reduced DAO activity. The other, rs1049748, is associated with increased DAO activity.

However, these mutations were not the direct cause of histamine intolerance. These SNPs frequently appear in the healthy population (controls) and the population with histamine intolerance. If someone has one of these four mutations, then she is not more likely to suffer from histamine intolerance.


DAO and Genetic Mutations

Patients with rs2052129, rs2268999, rs10156191, and rs1049742 SNPs are more likely to have reduced activity of DAO in blood cells. This means that although they cause a reduction in DAO activity, this reduction alone is insufficient to bring about histamine intolerance.

Four polymorphisms were also moderately associated with drug intolerance (rs2071514, rs1049793, rs2071517, rs11978239) but not with DAO activity.

Although the study found that four SNPs were associated with reduced DAO activity and symptoms in patients with histamine intolerance, these four SNPs alone are insufficient to cause an individual to have HIT.


histamine intolerance, mast cell activation, autoimmunity, Alison Vickery, Health, Australia


Genetic variations are definitively responsible for variations in DAO activity. Some SNPs increase, while others decrease it.

But DAO activity does not cause histamine intolerance. Even half the patients with histamine intolerance don’t have reduced levels of DAO.

A reliable biomarker for the diagnosis remains elusive, as plasma histamine is unstable. DAO serum activity is decreased only in half of the patients with histamine intolerance but also in about 17% of healthy controls.

Maintz and Novak et al. conclude that there appears to be a complex interaction between environmental factors (such as pathogens, medication, or alcohol) and other associated genetic defects (such as HNMT).

This correlates strongly with my clinical experience. A detailed understanding of the environmental factors linked to histamine intolerance and mast cell activation based on testing hundreds of people can be found in my FREE Course, The Roadmap to Resolution.

Health can be restored by removing the environmental factors causing the body to release histamine.


Additional Reading

Maintz L, Yu C-F, Rodiguez E, Baurecht H, Bieber T, Illig T, Weidinger S, Novak N. Association of single nucleotide polymorphisms in the diamine oxidase gene with diamine oxidase serum activities. Allergy 2011; 66: 893–902.

Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr 2007; 85:1185–1196.