Histamine genetics (HNMT and DAO)

Histamine genetics examines five variants in two genes whose enzymes break down histamine: in the AOC1 gene, which produces diamine oxidase (DAO), and in the HNMT gene for histamine N-methyltransferase. Commonly examined are the variants rs10156191, rs1049742, rs1049793 and rs2052129 in AOC1 and the variant Thr105Ile (rs11558538) in HNMT; the exact selection is stated in the report. The sample is EDTA blood; as a genetic test, written consent is required. Unlike measuring DAO activity in blood or histamine in stool, the genetic test does not show a current value but the inherited make-up – it stays the same for life.

How DAO and HNMT break down histamine

Histamine is inactivated by two separate pathways. DAO is produced mainly in the villus tips of the small-intestinal lining, in the kidneys and, during pregnancy, in the placenta; it is released outwards and breaks down histamine from food and gut bacteria before it passes through the gut wall. HNMT, by contrast, works inside cells, for example in the liver, kidneys, airways and skin. It transfers a methyl group from S-adenosylmethionine to histamine, producing N-methylhistamine, which is excreted in urine. In the brain, where there is no DAO, HNMT is the only breakdown route for histamine, which acts there as a messenger for wakefulness.

What do variants in the DAO gene (AOC1) mean for histamine breakdown?

The variants rs10156191, rs1049742 and rs1049793 each exchange one amino acid in the enzyme; rs2052129 lies in the gene's control region. For several of these variants, studies observed lower average DAO activity in blood – more markedly when both gene copies were affected or several variants occurred together. Less DAO means that histamine from histamine-rich meals is broken down more slowly and passes more readily through the gut wall into the blood. There it acts via its receptors: vessels widen, skin and mucous membranes swell and itch, and the gut contracts more strongly. Actual DAO activity, however, depends just as much on the condition of the small-intestinal lining.

What does the HNMT variant Thr105Ile mean for metabolism?

In Thr105Ile, threonine is replaced by isoleucine at position 105 of the enzyme. In laboratory studies the Ile form was less stable and less active, and people with this form had lower average HNMT activity. Histamine is then methylated more slowly inside the cells. How this affects the body is not clear-cut: studies on links with migraine, asthma or intolerance reactions have produced differing results. The Ile form is less common than the Thr form in European populations. Because HNMT uses up S-adenosylmethionine, its output also depends on the supply of methyl groups.

No variants found – what does it mean for histamine breakdown?

If none of the variants tested for are found, the inherited make-up of both enzymes is unremarkable. Symptoms after histamine-rich meals can still occur, because DAO activity also falls when the small-intestinal lining is irritated or damaged, for example after gut infections, in coeliac disease or in chronic inflammatory bowel disease; alcohol and some medicines inhibit the enzyme. In addition, some gut bacteria produce histamine themselves. The current state of histamine breakdown is therefore shown by measuring DAO activity, histamine in stool and N-methylhistamine in urine – they have their own pages.

The interpretation is given in your report.