The cheese effect and your genes.

Subtitled: Let’s all try not to have a heart attack this Christmas!

Let me set the scene:
You’re gathered ’round on Christmas Eve for a get together with all of your family, having traveled from far and wide. Your uncle brings his “special family recipe” of summer sausage to share, paired with a plate of all kinds of fancy cheeses. Your hipster cousin contributes some home-brew beer to the party, and you sop up all the alcohol with sourdough bread rounds stacked with sausage and cheese. That weird aunt from California brings in a tray of fermented foods (for your gut microbiome, of course) along with an olive and anti-pasta tray.  Let’s top it all off with your dad pulling out some anchovies, and your mom making a bowl of guacamole from some nice ripe avocados. Naturally, dark chocolate abounds in the chocolate covered peanuts and dried fruits.

Delicious and wonderful family fun.

Until… all the tyramine in those foods spikes your blood pressure, causing a severe headache, difficulty thinking, blurred vision, chest pain, nausea, and stroke-like symptoms!  Unfortunately, you drew the short end of the genetic straw when it comes to the genes that break down tyramine.


Back to the science:
A tyramine hypertensive crisis, also called ‘cheese effect’, is caused by overindulging in foods high in tyramine. This is usually associated with being on an MAO inhibitor. (People on MAOI are usually well aware of the dietary restriction of tyramine.) The cheese effect basically is caused by too much tyramine causing a sudden increase in blood pressure.

This article will dig into some of the genetic variants that can cause you to not break down tyramine as well as you should.

What is tyramine?
Tyramine is a biogenic amine, which refers to its chemical structure with nitrogen at its base. It is naturally found in trace levels in the body. We have lots of these biogenic amines produced in the body. Your body produced many of the amines in larger quantities, such as histamine, dopamine, epinephrine, norepinephrine, and these amines act mainly as neurotransmitters.

Tyramine can also be found in foods – especially fermented foods or foods that are close to spoiling. This is where the ‘cheese effect’ comes into play. (Read the background on how it was discovered)

A quick list of foods high in tyramine include:

  • aged, smoked, or fermented meats (salami, pepperoni, cured sausages, bacon, corned beef, beef jerky, etc)
  • aged cheeses (cheddar, gouda, Swiss, parmesan, feta, Brie, etc)
  • sourdough bread and some homemade yeast bread
  • marmite and other yeasty things
  • fermented veggies and dried fruits (sauerkraut, kimchee, tofu, soy sauce)
  • some beers and wines (especially unpasteurized beer such as homemade or tap)
  • medium sources include: olives, chocolate, snow peas, edamame, avocados, bananas, pineapple, eggplant, figs, yogurt, sour cream, peanuts, Brazil nuts, fava beans (broad beans)

Breaking down tyramine:
Tyramine that is absorbed in the intestines (from food and your microbiome) is mainly broken down in the body using the enzymes MAO-A, FMO3, and CYP2D6.

MAO-A is the enzyme that metabolizes a lot of neurotransmitters also, so inhibiting or decreasing MAO-A is one way to increase dopamine levels. Thus MAO-A inhibitors can be used as anti-depressants, although they usually aren’t the first choice due to the dietary interactions with tyramine.

If you get too much tyramine due to eating foods high in tyramine and not breaking down the tyramine (e.g. when taking an MAO-A inhibitor), it can throw your body into a hypertensive crisis, raising systolic blood pressure 30 mmHg or more. This is called the ‘tyramine pressor response’.  Tyramine is taking the place of other neurotransmitters, which triggers the body to release a bunch of norepinephrine, constricting blood vessels and raising blood pressure.  (Some of the first studies on the pressor effect raising blood pressure were done in the early 1900s using rotting horse meat.[ref] So don’t eat rotting horse meat…)

You may be wondering why we all aren’t dropping dead of a heart attack after eating a salami and cheese sandwich on sourdough. First, most people break down tyramine fairly well. There are three different enzyme pathways to take care of it. Second, repeated exposure to tyramine will decrease the tyramine pressor response. It’s the change from typically not eating foods high in tyramine to suddenly chowing down on them that can cause a response. For instance, eating a healthy diet full of fresh foods — and then hitting the holiday buffet and having salami, cheese, and olives, chased with a glass of red wine.

For people susceptible to migraines, the list of foods high in tyramine may correspond to your list of ‘triggers’. Many people with either cluster headaches or migraines don’t break down tyramine as well as they should.[ref] The vasoconstriction may be what is triggering the migraine.[ref][ref]

One final interesting tidbit… Tyramine is chemically similar to amphetamine and methamphetamine, although it doesn’t produce the same effects. The state of Florida banned tyramine as a schedule I drug in 2012. I’m not sure if this means that selling chocolate and cheese is a felony in FL or not.[ref]

Genetic variants that impair tyramine breakdown:
There aren’t any specific studies that say “if you have these genetic variants you will have cheese syndrome with high tyramine foods”. Instead, all of these variants have been studied in reference to their impact on enzyme activity in the molecules that metabolize tyramine.  Reduced enzyme activity in just one gene is not likely to cause you a whole lot of problems with high tyramine foods since there are three different ways your body can break it down. But reduced activity in a couple of the genes theoretically could cause problems with tyramine metabolism. Again, this all depends on your diet and how often you eat foods high in tyramine.

Tyramine that is taken in from food is mainly broken down in the liver using the enzymes MAOA, FMO3, and CYP2D6.[ref]

MAO-A genetic variants:
The monoamine oxidase A (MAOA) enzyme breaks down tyramine, serotonin, dopamine, epinephrine, and norepinephrine. It is located on the X chromosome, so males will only have one copy of the gene.

Check your genetic data for rs6323 (23andMe v4 only):

  • G/G or G: normal
  • G/T: somewhat reduced MAOA activity
  • T/T or T: reduced MAOA activity[ref][ref]

 

FMO3 genetic variants:
This is one of the main liver enzymes for breaking down tyramine (as well as other biogenic amines). FMO3, or flavin-containing monooxygenase 3, is dependent on FAD and FMN as cofactors.

These first four variants are more significant reductions in enzyme activity and are linked to TMAU (fish odor or strong body odor). Note that 23andMe doesn’t cover all the FMO3 variants that decrease the function.

Check your genetic data for rs28363581 (23andMe v4, v5; AncestryDNA):

  • C/C: decreased FMO3 function
  • C/T: decreased FMO3 function
  • T/T: normal FMO3 function

Check your genetic data for rs3832024 (23andMe v5 only):

  • DD or -/-: decreased FMO3 function[ref]
  • DI or -/TG: decreased FMO3 function
  • II or TG/TG: normal FMO3 function

Check your genetic data for rs61753344 (23andMe v4, v5; AncestryDNA):

  • T/T: decreased FMO3 function[ref]
  • G/T: decreased FMO3 function
  • G/G: normal FMO3 function

Check your genetic data for rs1736557 (23andMe v4, v5; AncestryDNA):

  • A/A: decreased FMO3 function[ref]
  • A/G: decreased FMO3 function
  • G/G: normal FMO3 function

Check your genetic data for rs2266780 (23andMe v4, v5; AncestryDNA):

  • G/G: somewhat decreased FMO3 function [ref]
  • A/G: somewhat decreased FMO3 function
  • A/A: normal FMO3 function

Check your genetic data for rs2266782 (23andMe v4, v5):

  • A/A: decreased FMO3 function [ref][ref] increased risk of hypertension, especially in smokers [ref]
  • A/G: somewhat decreased FMO3 function
  • G/G: normal FMO3 function

Check your genetic data for rs909530 (23andMe v4; AncestryDNA):

  • T/T: somewhat decreased FMO3 function [ref] (probably mild)
  • C/T: somewhat decreased FMO3 function
  • C/C: normal FMO3 function

Check your genetic data for rs909531 (23andMe v4):

  • C/C: somewhat decreased FMO3 function [ref]
  • C/T: somewhat decreased FMO3 function
  • T/T: normal FMO3 function

 

CYP2D6 genetic variants:
Inhibiting CYP2D6 causes tyramine elimination rates to decrease. [ref] There are several genetic variants that decrease or eliminate the CYP2D6 enzyme. These variants are not all that common, and carrying a variant that decreases the CYP2D6 enzyme can decrease your ability to break down tyramine as well as quite a few other drugs.

Check your genetic data for rs3892097 (23andMev4 only):

  • T/T: CYP2D6*4 – poor metabolizer
  • C/T:  typically an intermediate metabolizer
  • C/C: extensive metabolizer

Check your genetic data for rs5030655 (23andMe v4, v5):

  • -/- (or DD) : CYP2A6*6 – deletion, poor metabolizer
  • – /A (or DI):  intermedia metabolizer
  • A/A (or II): normal

Check your genetic data for rs1065852 (23andMe v4 only):

  • A/A: decreased or non-functioning
  • A/G:  somewhat decreased
  • G/G: normal

Check your genetic data for rs1135824 (23andMe v4, v5):

  • T/T: normal
  • C/T:  one copy of CYP2D6*3
  • C/C: two copies of CYP2D6*3, non-functioning

Check your genetic data for rs5030867 (23andMe v4, v5 ):

  • T/T: normal
  • G/T:  carrier of one CYP2D6*7 allele
  • G/G: carrier of two CYP2D6*7, non-functioning

Check your genetic data for rs5030656 (23andMe v4, v5):

  • C/T/T / C/T/T (or II): normal
  • -/C/T/T (or DI):  carrier of one CYP2D6*9 allele
  •  -/ – (or II): carrier of two CYP2D6*9, non-functioning

Check your genetic data for rs28371706 (23andMe v4 only):

  •  G/G: normal
  •  A/G:  carrier of one decreased or non-functioning allele
  •  A/A: possibly decreased or non-functioning

Check your  23andMe results for i4001479 (v4 only) or genetic data for rs72549354 :

  • -/- (or DD): normal
  • -/C (or DI): reduced enzyme activity
  • C/C (or II): no enzyme activity CYP2D6*20

Lifehacks:

Vitamin B2 (riboflavin) is important for people with FMO3 genetic variants.[ref][ref]  Make sure you are getting enough riboflavin via your diet, or consider supplementing with riboflavin.

Try a diet lower in tyramine. There are several good lists of foods to avoid in the ‘Read more’ section below.

Eat fresh foods! In addition to being found in fermented and aged food, tyramine builds up in leftovers. So if you aren’t going to eat your leftover dinner the next morning, go ahead an put it in the freezer.

If you get a lot of migraines, keep track of what you are eating either in a journal or through an app like Cron-o-meter. This will let you see if your migraines are related to tyramine-containing foods.

Receptors for tyramine (TA/AR1) are also found in the stomach, specifically in the pylorus, which is where the stomach dumps into the small intestines. Activation of the tyramine receptors in the pylorus cause gastric secretion – e.g. stomach acid secretion. This may cause some people to have a stomach that is sensitive to tyramine in foods.

Note that FMO3 and CYP2D6 are also involved in the metabolism of many other drugs. You should check out the list of substrates for FMO3 and CYP2D6 if you have variants that significantly affect their function. For example, you really shouldn’t do meth if you have FMO3 variants…  or at all, for that matter!

More to read:

3 Comments on “The cheese effect and your genes.

  1. What are the genetic or metabolic differences between tyramine and histamine? Mostly people lump all the amines together. I’m histamine intolerant (confirmed by my MD). I’m homozygous for MAO-A and heterozygous for one of the top 4 FMO3s (rs1736557). The foods to avoid for histamine intolerance are pretty much identical to those for tyramine intolerance. I’m also super reactive to most medications (never tried recreational drugs, never will). And of course chemical toxins like perfume and pesticides and food additives.

    • Hi Cyndi –
      The food lists definitely overlap a lot for histamine and tyramine. The difference here is probably in the outcome – while histamine reactions may give all the various histamine related symptoms including anaphylaxis, the sudden increase in blood pressure from too much tyramine may be a key indicator that the reaction is to tyramine instead of histamine. Practically, though, it doesn’t make much of a difference as to whether it is the tyramine or the histamine (or both!) in the pepperoni pizza and wine.
      Debbie

      • Histamine intolerance can also raise blood pressure. It’s quite well documented in medical sources.

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