Trimethylaminuria: Genetic variants that cause a malodorous body odor

Often referred to as ‘fish odor disease’, trimethylaminuria causes a strong odor in sweat, urine, and breath. While it may be easy to make jokes about, trimethylaminuria can have a serious impact on a person’s social and mental wellbeing, especially during childhood.

This article explores the FMO3 gene, which encodes the enzyme that breaks down trimethylamine. I’ll explain how to check your 23andMe or AncestryDNA data and then end with a few lifehacks that may help with managing the enzyme deficiency.

FMO3 gene and trimethylaminuria (TMAU)

Trimethylaminuria is a metabolic disorder caused by high levels of trimethylamine, which has a distinctive odor.

Trimethylamine (TMA) forms in the intestines from various nutritional substrates when intestinal bacteria break down choline, carnitine, betaine, and ergothioneine. TMA then absorbs into the bloodstream from the intestines.[ref]

Foods high in the precursors for trimethylamine (TMA) include:[ref]

  • eggs
  • liver
  • kidney
  • peas
  • beans
  • peanuts
  • Brussels sprouts, broccoli, cabbage, cauliflower
  • lecithin
  • soy products
  • some mushrooms (ergothioneine)

Gut bacteria act upon the foods containing the TMA precursors to produce the trimethylamine. After TMA is absorbed in the intestines, the FMO3 enzyme converts it into TMAO (trimethylamine-N-oxide).[ref]

TMAO (trimethylamine-N-oxide) is the oxidized form of trimethylamine (TMA). Several problems linked to it include lipid homeostasis, diabetes, and heart health.

The drawback of high TMAO: A number of studies link higher plasma TMAO levels to an increased relative risk of thrombosis (heart attack, stroke). Platelets become a little bit more sticky – more easily activated to clump together – when levels of TMAO are high.[ref]

Too little FMO3 causes the opposite problem. Trimethylaminuria (a.k.a. fish odor disease) results from not enough trimethylamine (TMA) converting into TMAO.

Balance is critical here… you don’t want too much TMAO because of heart disease, but you also don’t want too much TMA due to the odor.

People with trimethylaminuria (TMAU) have genetic mutations in the FMO3 gene that leads to decreased enzyme function, resulting in trimethylamine (TMA) remaining in the bloodstream. The TMA has a bad (sometimes fishy) smell that can exude from the body.

Thus, we need just the right amount of TMA to TMAO conversion.

Trimethylaminuria – strong body odor

The diagnosis of trimethylaminuria (TMAU) is based on a distinctive odor and high urinary TMA levels in comparison to TMAO. The amount of TMA will vary over the course of the day, depending on what a person eats (e.g. choline or other TMA precursors). Thus, measuring the ratio is a better way to know how much TMA is being converted to TMAO. In general, a ratio of (TMAO/(TMAO + TMA)) is below 0.8 in people with mutations in the FMO3 gene.[ref]

Odor caused by TMAU

Most research studies refer to the body odor in trimethylaminuria (TMAU) as a ‘fishy odor’ or ‘rotten fish’, but patients with TMAU sometimes describe the odor in different ways. To some people, it could smell like garbage, urine, or rotting eggs. Plus, the presence of the odor can vary based on diet and gut microbiome composition.

A study of people with particularly malodorous BO found that about a third of them had TMAU.[ref]

Is trimethylaminuria always genetic?

Primary trimethylaminuria (TMAU) occurs due to a mutation that causes the FMO3 gene not to function well. Two copies of FMO3 mutations are generally needed to cause trimethylaminuria. Sometimes, though, a stronger odor is noticed in people with one copy of a mutation, depending on diet and the gut microbiome.

But…the cause of trimethylaminuria may not always be genetic.

While primary TMAU is a genetic disease caused by mutations in the FMO3 gene, a transient form is also possible.

The FMO3 enzyme is produced mainly in the liver. Adults can acquire TMAU if they have liver cirrhosis or viral hepatitis, which impairs liver function.

Transient TMAU can occur during menstruation or when consuming high amounts of choline (TMA precursor).

People with a combination of several FMO3 common genetic variants are more likely to have transient TMAU.[ref]

What else does the FMO3 enzyme do?

Nicotine metabolism: Nicotine is mainly metabolized in the body using the CYP2A6 enzyme. But the FMO3 enzyme can also play a role in nicotine metabolism, especially in people who have genetic variants that cause low CYP2A6 activity. Additionally, people with genetic variants that slow the FMO3 enzyme function have an altered response to nicotine.[ref] (Check your CYP2A6 genetic variants.)

Drug metabolism: Certain drugs including, tamoxifen, and cimetidine (Tagamet) are metabolized using the FMO3 enzyme. Serious interactions can occur with FMO3 mutations and busulphan, which is used in stem cell transplants.[ref][ref]


Genetic variants in the FMO3 gene linked to TMAU:

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Common variants that decrease FMO3 enzyme function:

Carrying several copies of common FMO3 variants that decrease FMO3 function could cause mild, transient malodor, likely depending on choline in the diet and the gut microbiome.[ref]

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

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

Members: Your genotype for rs2266782 is .

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

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

Members: Your genotype for rs2266780 is .

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

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

Members: Your genotype for rs909530 is .

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

  • A/A: decreased FMO3 function[ref] may add to trimethylaminuria combined with other FMO3 variants[ref][ref]
  • A/G: decreased FMO3 function
  • G/G: typical FMO3 function

Members: Your genotype for rs1736557 is .

More severe impact on FMO3 enzyme function (rare mutations):

Traditionally, TMAU is referred to as an autosomal recessive disease, requiring two copies of a rare mutation in the FMO3 gene. Sometimes, though, a person who carries one copy of an FMO3 mutation will have transient trimethylaminuria, usually depending on diet. Additionally, a combination of a rare mutation along with several of the more common variants (above) may also result in trimethylaminuria.[ref]

Check your genetic data for rs72549332 (AncestryDNA):

  • A/A: trimethylaminuria possible in conjunction with a second mutation[ref]
  • A/G: decreased FMO3 function
  • G/G: typical

Members: Your genotype for rs72549332 is .

Check your genetic data for rs72549326 (AncestryDNA):

  • T/T: trimethylaminuria possible[ref]
  • C/T: decreased FMO3 function
  • C/C: typical

Members: Your genotype for rs72549326 is .

Check your genetic data for rs72549322 (AncestryDNA):

  • G/G: trimethylaminuria possible in conjunction with a second mutation[ref]
  • A/G: decreased FMO3 function
  • A/A: typical

Members: Your genotype for rs72549322 is .

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

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

Members: Your genotype for rs61753344 is .

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

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

Members: Your genotype for rs3832024 is .


Lifehacks for trimethylaminuria:

Below are some research-based diet and supplement recommendations that work for some people with TMAU. Talk with your doctor, of course, if you have been diagnosed with TMAU to find out what is right for you.

Riboflavin (vitamin B2):

One treatment for TMAU is vitamin B2, also known as riboflavin. B2 is needed in the conversion of TMA to TMAO, and increasing the supply of vitamin B2 helps a lot of people with trimethylaminuria.[ref][ref] (Learn more about riboflavin here.)

Probiotics:

While there are many anecdotal reports of probiotics helping with TMAU, I can’t find clinical trials supporting this. There is research on the archaea that live in the intestines as being important in the breakdown and consumption of TMA.[ref] This doesn’t seem to be an option, yet, as a supplement.

Low choline diet:

If you have problems with transient malodorous BO and are taking choline supplements, you may want to cut out the supplemental choline to see if it solves your problem.

The first line of treatment for someone diagnosed with TMAU is often a low choline diet. Choline is really important, though, for a lot of cellular functions. For a child with TMAU, the low choline diet should be supervised by a doctor and dietician because choline is vital in the growing brain. Choline is also essential for anyone planning on getting pregnant.

Limiting fish in the diet:

Salt-water fish contain TMAO. Consuming a lot of fish can lead to an alteration in the ratio of TMA to TMAO – sometimes resulting in too much TMA. For people with trimethylaminuria, a diet that avoids fish and seafood is recommended.[ref]

Avoiding carnitine supplements:

Carnitine can also be a precursor for TMA. If you are supplementing with carnitine (e.g. weight lifting supplements) and have a problem with malodorous BO, try cutting out the supplement to see if it helps.[ref]

Washing with a low pH soap:

The TMA that causes the odor is the volatile version of the compound. It turns out that lower pH on the skin reduces the amount of the volatile (odiferous) compound.[ref] Of course, be careful not to cause skin damage by going too acidic. There are a number of cleansers and body washes available that have a lower pH – just do a google search. This is the same concept of why you sometimes soak fish in lemon juice or a little bit of vinegar to get rid of the ‘fishy’ smell.


Related Articles and Genes:

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The cheese effect and your genes: tyramine intolerance
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Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.