A new study by Maintz and Novak et al concludes that the histamine intolerance and diamine oxidase connection alone does not explain histamine intolerance (HIT). Previously, genetic mutations in DAO, were hypothesised to be the sole cause.

Histamine Intolerance

HIT is the result of an imbalance between histamine and the capacity for histamine degradation.

There are two major 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 undertook a study of 285 patients with HIT and 199 healthy individuals (controls) to evaluate whether DAO gene variants (SNPs) could explain HIT. Furthermore, they tried to find out whether these SNPS were associated with decreased or increased DAO activity.

Here are the major results:

Reduced DAO

DAO activity is highly variable amongst the general population.

Patients with HIT are more likely to have reduced levels of DAO activity (50% of patients with HIT, 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 that had HIT had reduced levels of DAO activity.

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 appear as frequently in the healthy population (controls) as well as in the population with HIT. If someone has one of these four mutations, than he is not more likely to suffer from HIT.

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 not sufficient to bring about HIT.

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 HIT, these four SNPs on their own are not sufficient to cause an individual to have HIT.


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

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

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

This means that HIT remains a complex and largely unexplored disease which is difficult to diagnose precisely. A reliable biomarker for the diagnosis remains illusive, as plasma histamine is very unstable, and DAO serum activity is decreased only in half of the patients with HIT, but also in about 17% of healthy controls.

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.


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