BChE – Pesticides, Parkinson’s, and Potatoes

The BCHE gene codes for the butyrylcholinesterase enzyme. The BChE enzyme is found in the plasma of the blood, and it is a cholinesterase which breaks apart choline esters, such as acetylcholine.

Acetylcholinesterase is a similar enzyme that is responsible for breaking down the neurotransmitter, acetylcholine in the synapses of nerves. It is kind of like the ‘off switch’ for stopping a neuron from firing repeatedly.

Genetic variants of the BChE gene can cause a decrease in enzyme activity. This can lead to various and seemingly unconnected consequences…

Background on BCHE

Butyrylcholinesterase (BChE) is found in the plasma and can breakdown acetylcholine (similarly to acetylcholinesterase). Since it is found in the bloodstream, though, it doesn’t act within neurons like acetylcholinesterase (AChE) does. (In the synapse of a neuron, acetylcholine causes it to fire, contracting a muscle. AChE breaks down the acetylcholine, letting the muscle relax. This all happens in an instance.)

BChE levels become important when exposed to certain types of anesthesia. It controls the rate for the breakdown of succinylcholine, which is a muscle relaxant used during surgery.

BChE also plays a role in the cholinergic anti-inflammatory system. This is a one-way system by which the brain can signal and control the immune response through the vagus nerve.  Macrophages have acetylcholine receptors on their surface, and acetylcholine can then initiate part of the immune response. AChE and BChE can then turn off the immune activation when it is no longer needed.  [ref]

AChE and BChE inactivating acetylcholine which was released from the vagus nerve and acted on a macrophage. Creative Commons license. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4100123/

BChE, being in the plasma, can be important in the immune response, especially when AChE is inhibited.

Too much inhibition of AChE results in death. Muscles need to relax – especially those controlling respiration – and excessive inhibition of AChE causes asphyxiation.

AChE inhibitors are a type of medication used in Alzheimer’s disease and glaucoma in very controlled amounts. They can also be used with anesthesia. Snake venom and the nerve gases, sarin and VX, are also AChE inhibitors. And pesticides such as organophosphates and carbamates are AChE inhibitors.

Pesticides and Parkinson’s

Organophosphates are a class of insecticide that is commonly used in agriculture, veterinarian use, home pest control, and for mosquito control. They are the most commonly used type of pesticide. Specific organophosphates include malathion (lice, mosquitos), chlorpyrifos (worms, termites), parathion (banned in a lot of countries), diazinon (agricultural insecticide), fenitrothion (chewing and sucking insects), dichlorvos, and ethion. [ref][ref][ref][ref]

Carbamates are another commonly used type of insecticide. Carbamyl (Sevin) is carbamate that is widely used as an insecticide in home and agricultural use.

Organophosphates and carbamates work to kill insects by inhibiting AChE.  Organophosphates are irreversible ACheE inhibitors, while carbamates are less toxic and reversible.

Pesticide exposure has long been linked to Parkinson’s disease. Chlorpyrifos and other organophosphates increase the risk of Parkinson’s disease, depending on the amount of exposure and the genetic variants the person carries. [ref][ref][ref]  And one of those genetic variants that increases the risk of Parkinson’s due to pesticide exposure is in the BChE gene.


So how do potatoes relate to pesticides and Parkinson’s?

One component of potatoes is a glycoalkaloid compound called α-solanine. The compound is found in the leaves and stems as well as in the tuber that we eat. When potatoes are exposed to light, they turn green due to increased α-solanine. (Green potatoes are toxic – don’t eat them!)[ref]

Potatoes are part of the nightshade family. All of the nightshade family produces varying amounts of glycoalkaloids, which are AChE inhibitors. [ref][ref]

Edible nightshades include potatoes, tomatoes, eggplant, and peppers.

It is theorized that BChE variants interact with the alkaloid compounds in nightshades — but that depends a lot on the amount eaten along with other possible AChE inhibitors. [ref]

When is cholinesterase inhibition a good thing?

While too much of a cholinesterase inhibitor is obviously bad (death is never a good side-effect), a minor inhibition of cholinesterases can be beneficial in some circumstances.

Extending the time that a neuron is exposed to acetylcholine can be beneficial in some cases of Alzheimer’s disease. It also can increase REM sleep, which could be beneficial at times in relation to learning and memory. Cholinesterase inhibitors are also sometimes prescribed for schizophrenia. [ref][ref]

The dose makes the poison is a well-known saying. The right amount of cholinesterase inhibition can be beneficial in certain circumstances. Which leads me to think that carrying a genetic variant that decreases BChE could be beneficial in some ways – and thus explains why a BChE variant that mildly decreases enzyme function is common in the human population.

Genetic Variants of BChE:

The K-variant of BChE decreases the production of the enzyme by 33%. This is a fairly common variant, and up to 30% of some populations carry the k-variant.

Check your genetic data for rs1803274 (23andMe v4, v5):

  • C/C: normal
  • C/T: one copy of the K-variant, decreased BChE, possibly more sensitive to nightshades, increased risk of Parkinson’s with organophosphate exposure
  • TT: two copies of the K-variant, decreased BChE, possibly sensitive to nightshades, increased risk of Parkinson’s with organophosphate exposure [ref][ref][ref]

The A-variant is a more severe change in the BChE enzyme function. About 2% – 5% of some populations carry one copy of the A-variant.

Check your genetic data for rs1799807 (23andMe v4, v5; AncestryDNA):

  • T/T: normal
  • C/T: one copy of A-variant, may have delayed recovery from succinylcholine, increased risk of leprosy [ref][ref][ref]
  • C/C: two copies of A-variant (very rare)


If you carry one of the BChE variants, you should avoid exposure to nerve gas…

Avoiding Organophosphates

Parkinson’s risk is significantly increased in people with the BChE K-variant and exposure to organophosphates. Eating organic, watching your exposure to pesticides (such as spraying for mosquitos), and avoid using pesticides in your home can reduce your exposure to organophosphates.

If you are interested in knowing which pesticides are commonly detected on foods in the US by the FDA, check out the What’s On My Food website.  The Environmental Working Group puts out a yearly list of the fruits and vegetables found with the most pesticide residue.

Try Eliminating Nightshades 

The alkaloids in nightshades are theorized to cause some people to have aching joints and muscle stiffness. These alkaloids interact with the BChE enzyme and carriers of the variants may be more likely to have problems with excessive nightshade intake.

An easy way to know if this is a problem for you is to stop eating nightshades (potatoes, tomatoes, peppers, eggplant, goji berries) for a few days. See how you feel.  Then eat a potato with the skin on it. Perhaps top it with some salsa…

Removing the skins of potatoes (and especially the eyes) cuts down on the alkaloid content. Ripe tomatoes have significantly less alkaloid content (alpha-tomatine) than green tomatoes.  [ref]

Anesthesia complications:

People carrying the BChE k-variant have a delayed recovery from succinylcholine which is as a muscle relaxant when intubating patients under anesthesia. This can cause a delay in returning to normal function (a problem when that normal function involves breathing) But while the response is delayed, it isn’t by much in people who are heterozygous for the K-variant (less than a minute on average).  [ref]

The A-variant is linked to longer delays in returning to normal when succinylcholine is used. This can be more serious and you should tell your doctor if you carry the A-variant and are going to have surgery. The combo of the K-variant and the A variant can lead to more serious complications with succinylcholine.[ref][ref][ref]


Alzheimer’s risk may be increased in people carrying the BChE K-variant. And people who are homozygous for the K-variant may have a negative response to AChE inhibitors for Alzheimer’s disease. In fact, BChE k-variant carriers had worsening symptoms with the medication donepezil.[ref][ref]

More to read:

Gulf War Illness: Genetic susceptibility and current research

Using your genetic data to solve sleep problems

A good night’s sleep is invaluable, literally priceless — but so many people know the frustration of not being able to regularly sleep well.

And not getting enough sleep can lead to many chronic diseases such as diabetes, obesity, dementia, and heart disease. Sleep really is that important!

There are many factors involved in sleeping well, and genetics plays a role in some sleep disorders.

Looking at the genetic basis of sleep disorders may give you ideas on which path to take to fix the problem.

What is sleep and why do we need it?

So this turns out to be a more difficult question to answer than you would think.

We are asleep for about a third of our lives. All animals, both big and small, sleep. So you would think that scientists would know exactly why and how sleep works…  Instead, we have almost as many questions about sleep as we have answers.

Let’s look at the definition of sleep from a prominent sleep medicine textbook: “Sleep is a recurring, reversible neuro-behavioral state of relative perceptual disengagement from and unresponsiveness to the environment. Sleep is typically accompanied (in humans) by postural recumbence, behavioral quiescence, and closed eyes.”[ref]

Yep – big words for laying down, closing your eyes, and going to sleep.  The important thing here, though, is what goes on in the brain while you sleep.  While your body is inactive (hopefully), your brain is doing some pretty cool and weird stuff while you sleep. And there are different metabolic processes going on in your body while you are asleep.

Why is sleep so important? 

While you sleep, your brain consolidates memories — it makes the things that you learned during the day stick in your brain. This has been known for a long time and is something that researchers frequently experiment with.[ref]  Recently, researchers experimented with just decreasing certain stages of sleep and showed that the neuroplastic changes to the brain in learning happen specifically during deep sleep.[ref]

Studies of sleep deprivation show that there can be devastating consequences.

  • In general, sleep deprivation causes a decrease in speed and accuracy in tests for attention, working memory, processing speed, short-term memory, and reasoning. [ref]
  • One-third of accidents in a survey of commercial truck drivers were caused by drowsy driving due to sleep deprivation. [ref]
  • According to the NTSB, going more than 20 hours without sleep is equivalent to driving legally drunk. And your risk of being in a car crash goes up 3-fold! [ref]
  • This pretty much sums of the rest of the effects of sleep deprivation: ‘studies have shown that short sleep duration is associated with increased incidence of cardiovascular diseases, such as coronary artery disease, hypertension, arrhythmias, diabetes and obesity, after adjustment for socioeconomic and demographic risk factors and comorbidities.’ [ref]

Stages of sleep:

When you sleep, your brain goes through different periods of activity. These are categorized into slow-wave sleep and REM (rapid eye movement) sleep.  Slow wave sleep can further be broken down into deeps sleep and lighter sleep.  About 50% of sleep in adults is the light, non-REM sleep.

Most of your deep sleep comes during the early part of the night, while the latter half of the night has much more REM sleep. [ref]

What causes you to feel sleepy:

We feel the need to sleep each night due to two causes: our natural circadian rhythm and increased homeostatic sleep drive.

The homeostatic sleep drive is what researchers call the build up over the course of the day for the need to sleep. This is mainly driven by a build-up of adenosine in the brain, which is then cleared out during sleep.  Adenosine is part of the ATP (adenosine triphosphate) molecule which is used for cellular energy. As you use energy over the course of the day, you build up adenosine in the brain. (Caffeine makes you feel more awake by blocking the adenosine receptors) [ref]

Genes and Sleep Disturbance:

A recent genome-wide analysis of sleep duration, timing, and disturbances found that there was an overlap between sleep quality and the genetic variants that are associated with sleep disorders. The study was done using data from 5000+ people wearing sleep trackers, and then it was replicated [ref]

Morning Grogginess and the ADA gene:

Not clearing out adenosine quickly enough overnight can cause a person to still feel groggy when they wake up in the morning.  A variant of the ADA (adenosine deaminase) gene is associated with reduced activity which causes adenosine to be cleared away less quickly.

Check your genetic data for rs73598374 (23andMe v4, v5; AncestryDNA)::

  • C/C: normal clearance of adenosine
  • C/T: reduced clearance of adenosine, more deep sleep but may feel sleepy when waking up[ref]
  • T/T: reduce clearance of adenosine, more deep sleep but may feel sleepy when waking up

Restless Leg Syndrome and Periodic Limb Movement Disorder

Restless Leg Syndrome (RLS) is a fairly common disorder affecting about 10% of the US population. Periodic Limb Movement Disorder -PLMD (also called Periodic Limb Movements In Sleep – PLMS) is often lumped together with RLS in studies. The two often go together with about 80%-90% of RLS suffers also having PLMD.[ref]

About 40% – 60% of people with RLS have a family history of it, suggesting a strong genetic component. People with a family history of RLS tend to get it at a younger age.[ref]  In general, RLS is more likely to be found in women, in older people, and in those with iron storage issues. [ref]

People with restless leg syndrome are at an increased risk of psychiatric disorders. One study showed that 37% of people with RLS met the criteria for a psychiatric disorder – compared to only 15% of people without RLS. [ref]

MEIS1 gene:
The MEIS1 gene has been studied for restless leg syndrome.  MEIS1 encodes a homeobox protein. (Homeobox genes are involved in forming organs and limbs in embryonic development.) There are several MEIS1 SNPs that have been linked to an increased risk of RLS and PLMD.

Check your genetic data for rs2300478 (23andMe v4, v5; AncestryDNA):

  • G/G: greater than 1.7x risk of RLS, increased sympathovagal balance during N3 sleep stage[ref][ref]
  • G/T: 1.7x risk of RLS
  • T/T: normal risk of RLS

BTBD9 gene:

Check your genetic data for rs3923809:  (23andMe v4, v5; AncestryDNA):

  • A/A: approx. 50% with this genotype will have RLS, 1.9x risk of PLMD without RLS, serum ferritin levels decreased  26%  [ref]
  • A/G: higher risk of RLS and PLMD, serum ferritin levels decreased 13%
  • G/G: normal risk of RLS

Check your genetic data for rs9357271 (23andMe v4, v5; AncestryDNA):

  • C/C: lower risk (<0.63) of RLS  [ref]
  • C/T: slightly lower risk of RLS
  • T/T: normal risk of RLS

PTPRD gene:

Check your genetic data for rs1975197 (23andMe v4, v5; AncestryDNA):

  • A/A: increased (1.8x) risk of RLS  [ref]
  • A/G: increased risk of RLS
  • G/G: normal risk of RLS

GABA Receptors:

A study of patients with restless leg found that GABA receptor variants may affect restless leg syndrome. GABA is the main inhibitory neurotransmitter — it keeps the neurons from being overexcited.[ref]

Check your genetic data for rs2229940 (23andMe v4, v5; AncestryDNA):

  • G/G: normal
  • G/T: earlier age of onset for RLS
  • T/T: earlier age of onset for RLS[ref]  (also, faster motor reaction times [ref])

Narcolepsy Genes:

Narcolepsy, or excessive daytime sleepiness, is found in about 1 in every 2,000 people in the US.  It is now thought to be an autoimmune disease and is associated with HLA-DRB1*1501 and HLA-DQB1*0602. HLA-DRB1*1501 is highly correlated with rs3135388 and found to influence the risk of several autoimmune diseases including MS, lupus, and narcolepsy. HLA-DQB1*0602 is found in 90% of people who have narcolepsy, but it can’t be determined by a single SNP that I have found.

Check your genetic data for rs3135388  (23andMe v4, v5; AncestryDNA):

  • A/A: (HLA-DRB1*1501) increased risk of narcolepsy, MS  [ref]
  • A/G: (one copy of HLA-DRB1*1501) increased risk of narcolepsy
  • G/G: normal risk

Check your genetic data for  rs1154155 (23andMe v4, v5; AncestryDNA):

  • G/G: increased risk of narcolepsy (2.5x increased risk) [ref]
  • G/T: increased risk of narcolepsy
  • T/T: normal

Circadian Rhythm Genes:

Our natural circadian clock is run by several core genes that rise and fall over a 24 hour period, setting the rhythm for all of our body’s functions. Sunlight hitting the retina in the morning resets the circadian clock.

Circadian rhythm disruptions have been tied to obesity, difficulty in losing weight, diabetes, Parkinson’s, Alzheimer’s, heart disease, and ADHD symptoms.

CLOCK gene:
The aptly named CLOCK gene is part of the core molecular circadian clock.

Check your genetic data for rs1801260 (23andMe v4, v5; AncestryDNA):

  • G/G: higher activity levels in the evening, delayed sleep onset. [ref][ref]
  • A/G: somewhat delayed sleep
  • A/A: normal


PER2 gene:
The PER2 (period 2) gene is part of your core molecular circadian clock.

Check your genetic data for rs35333999 (23andMe v4 only):

  • C/C: normal
  • C/T: likely to stay up later, evening chronotype, longer circadian period
  • T/T: likely to stay up later, evening chronotype, longer circadian period [ref]

AANAT gene:
AANAT (arylalkylamine N-acetyltransferase) controls the production of melatonin in the pineal gland. AANAT enzyme activity is high at night and tied to a person’s circadian rhythm. Polymorphisms in AANAT are more common in those with Delayed Sleep Phase Disorder (Japanese Study).

Check your genetic data for rs28936679 (23andMe v4 only):

  • A/G: higher risk of Delayed Sleep Phase Disorder [ref]
  • G/G: normal

Insomnia Genes:

The GSK3B gene is involved in both circadian rhythm and glucose metabolism. This is one gene that is influenced by lithium.

Check your genetic data for rs334558 (23andMe v4, v5; AncestryDNA):

  • G/G: increased risk for severe insomnia in depression [ref]
  • A/G: increased risk for severe insomnia in depression
  • A/A: normal

One of the core circadian clock genes, PER2, is associated with insomnia.

Check your genetic data for rs7602358 (23andMe v4 only):

  • G/G: increased risk for insomnia, especially with stress [ref]
  • G/T: increased risk for insomnia
  • T/T: normal risk for insomnia

Waking up really early and not being able to fall back to sleep is a form of insomnia known as sleep maintenance insomnia.  A variant in the TPH2 gene, which converts tryptophan into serotonin and then melatonin, has been associated with an increased risk of sleep maintenance insomnia. (

Check your genetic data for rs4290270 (23andMe v4 only):

  • T/T: increased risk of waking early, increased risk of depression [ref][ref]
  • A/T: probably a slightly increased risk of waking early, depression (this is the most common genotype)
  • A/A: normal



Overall sleep:

One small thing that will make a HUGE difference in sleep and circadian rhythm function is to block blue light at night. Our modern environment is full of light at night and especially in the blue wavelengths from LED bulbs, TV’s, and phones. The blue wavelength (~480nm) is the exact wavelength that resets our circadian genes each morning.

Other than changing all your light bulbs to red lights or going back to candlelight, your best bet for blocking the blue wavelengths at night is blue-blocking glasses. There are inexpensive options like the UVEX safety glasses or more stylish options like these Swannies.

Temperature is also important in sleep. Your body expects the temperature to drop when the sun goes down. Keep your bedroom as cool as you comfortably can at night. [ref]

Restless leg:

There are several new studies out that point to a role of adenosine in causing restless leg. [ref][ref]

Hops extract and valerian root combined can block the effects of caffeine on the adenosine receptors. Both are known for their sleep-promoting effects, and both can be found in OTC herbal remedies for sleep and restless leg.[ref[ref]

Near-infrared light therapy was shown in a small study to help with restless leg syndrome. [ref]

A medical device that puts pressure on the abductor hallucis and flexor hallucis brevis muscles was shown in a clinical trial to reduce sleep disturbances due to RLS. [ref]

A study showed that acupuncture plus gabapentin (prescription med for RLS) was more effective than gabapentin alone. [ref]

Transcutaneous spinal direct current stimulation has been shown to decrease RLS. [ref]

Morning Grogginess:

The ADA gene variant that causes morning grogginess (along with increased deep sleep) may indicate that you simply need to make sure that you get enough sleep. Most adults need between 7 and 8.5 hours of sleep per night. Try adding in an extra half hour of sleep time and see if it cures your morning grogginess. You may just need a little extra time each night to adequately clear adenosine.   (And yes, caffeine is an adenosine receptor antagonist and will probably make you feel much better on mornings when you haven’t gotten adequate sleep.)


More to read:

Circadian Rhythms: Genes at the Core of Our Internal Clocks

Circadian Rhythms: Of Owls, Larks, and Alarm Clocks

Narcolepsy, the Sleep Disorder, Linked to Immune System Problem

*article originally published July 2015, updated April 2019*

Problems with IBS? Personalized solutions based on your genes

We tend to take happy bowels for granted — until something goes awry!  For many people, a daily battle seems to wage in their intestines.

Pain, discomfort, bloating, diarrhea and/or constipation — known as IBS or irritable bowel syndrome.

There are multiple causes of IBS, and genetics can play a role in IBS symptoms. Pinpointing your cause can help you to figure out your solution.

Irritable Bowel Syndrome

IBS affects more than 10% of the population in Westernized countries [ref]

IBS is a functional GI disorder defined as having:

  • abdominal pain, bloating, gas
  • diarrhea (IBS-D)
  • constipation (IBS-C)
  • OR – a mix of diarrhea and constipation (IBS-M)

The diagnosis is often one of eliminating other conditions such as celiac, Crohn’s, or ulcerative colitis — and thus being left with IBS.

The causes of IBS are often a mystery — both to the person who has it and to their doctor. The word ‘idiopathic’ gets used a lot.  According to the National Institute of Health “Doctors aren’t sure what causes IBS.” [source]

Often people will go through a series of dietary changes, trying to figure out which foods, if any, lead to their problems.

Researchers have come up with many different ideas that can factor into IBS.  I’m going to dig into a few of these and show how they link up to genetics.

Digesting Carbs:

Carbs are supposed to be digested, broken down and absorbed, in the small intestines.  When that doesn’t happen — either due to lack of enzymes to break them down or increased gut motility — the carbs end up in the colon. Extra carbs in the colon feed the bacteria there, and they party all night, giving off gas.

While frank deficiencies of the enzymes that break down different carbohydrates are somewhat rare, researchers are now discovering that partial deficiencies could be causing IBS symptoms for some people.[ref]

Sucrase-isomaltase deficiency is a lack of the enzyme that breaks down the starches and sugars. SI deficiency leads to accumulation of unabsorbed carbs in the intestines. This leads to a change in the gut microbiome, increased short-chain fatty acids, increased gas, and often diarrhea, abdominal pain and bloating. [ref]

Lactose is a sugar found in milk and dairy products. Most people of European descent have inherited a genetic variant that still allows for the production of lactase as an adult. But for people who don’t produce lactase as an adult (e.g. most Asians, 10% of Caucasians), drinking milk may aggravate IBS symptoms.

Serotonin makes things move:

Most of the serotonin (5-hydroxytryptamine, 5-HT) your body produces is in the intestines. It acts both a neurotransmitter and immune system regulator. It is the signaling molecule that regulates motility, secretion, and vasodilation.  When the intestinal tract is stimulated, it produces more serotonin and more serotonin receptors.  [ref]

The microbes in the gut are able to influence the amount of serotonin synthesized there.[ref] So an overgrowth of certain bacteria could influence and increase serotonin synthesis. [ref]

There are several different serotonin receptors in the intestines. The overactivation of the 5-HT3R receptor has specifically been linked to IBS with diarrhea. One study showed that people with IBS-D had double the number of 5-HT3R in the intestinal mucosa, compared with a control group.[ref]

Bile acid synthesis:

Your body produces bile acids for digesting fats as well as for getting rid of waste products, such as bilirubin. Adults produce between 400 and 800 ml of bile per day.

Typically, the gallbladder stores bile when you haven’t recently eaten. Then it is released from the gallbladder into the upper part of the small intestines.  The bile acids then break up, or emulsify, fats so that they can be easily digested by lipases. [ref]

About 95% of the bile acids are reabsorbed when they reach the end of the small intestines.  They are recycled through the liver and then reused again.

If too much of the bile acid ends up in the colon, diarrhea will ensue…  This can be either from too much being produced or from not enough being reabsorbed at the end of the small intestines (at the ileum).

When excess bile acids reach the colon, they cause diarrhea by stimulating an increase in water in the stool.

Studies show that between 10 – 25% of patients with IBS-D had problems stemming from bile acids reaching the colon.[ref]

Enteric Nerve Irritation:

The nerves that cause peristalsis, or movement, in the intestines are called enteric nerves.  Several studies point to increased expression of TRPV1 in the enteric nerves of people with IBS. TRPV1 is a pain receptor and that also may play a role in the response to mechanical stimulation (i.e. foodstuff pressing on the intestines).

TRPV1 stands for transient receptor potential vanilloid type-1. It is also the receptor that capsaicin binds to, causing you to sense spicy heat. A study that looked at the TRPV1 receptors in biopsies from IBS patients found that they had a 3.5-fold increase compared to normal people. Basically, this causes hypersensitivity to pain in the intestines (irritability!). [ref]

Another study points to histamine as a possible cause of sensitized TRPV1 channels in IBS.[ref]  And to tie this back to bile acids, a study points to bile acids causing mast cells activation (releasing histamine) and increasing TRPV1 expression.[ref]

Variants in the TRPM8 gene have also been linked in large, genome-wide studies to increased risk of IBS-C. This transient receptor potential channel is also thought to be associated with bile acid secretion.  [ref]

Genetic Variants to Check

Genetics plays a role in susceptibility to IBS. It is likely that for most people IBS is caused by a combo of several genetic susceptibility variants along with environmental (or diet) factors. [ref]

Carbohydrates Metabolism Genes:

SI gene:  The SI gene codes for the enzyme sucrase-isomaltase, which metabolizes starches and sugars for absorption in the intestines. The rs9290264 variant is fairly common and about 30% of the population carries it. It is linked to a  decrease in enzyme activity and an increased risk of IBS-D (diarrhea subtype) and IBS-M (mixed diarrhea/constipation).

Even in people who don’t have IBS, the rs9290264 variant was associated with more frequent pooping. (Yes, there were 133 subjects who recorded their daily defecation patterns.)[ref]

Check your genetic data for rs9290264 (23andMe v4, v5; AncestryDNA)

  • C/C: normal
  • A/C: somewhat reduced enzyme activity, increased risk of IBS-D and IBS-M
  • A/A: reduced enzyme activity, 3.8x increased risk of IBS-D and IBS-M, increased daily defecation [ref][ref]


Lactose: This genetic variant will indicate whether you are likely to still produce lactase as an adult.

Check your genetic data for rs4988235 (23andMe v.4, v.5; AncestryDNA):

  • A/A: Still produces lactase as an adult
  • A/G: Still produces lactase as an adult, but less than those with A/A [ref]
  • G/G: No longer produces lactase as an adult

Serotonin genetic variants:

HTR3E gene: This gene codes a subunit of the 5-hydroxytryptamine receptor (serotonin receptor). It is mainly expressed in the gastrointestinal tract.

Check your genetic data for rs56109847 (23andMe v4, AncestryDNA):

  • G/G: normal
  • A/G: increased risk of IBS-D
  • A/A: 4 to 8 fold increased risk of IBS D[ref][ref]

Note that this SNP used to be called rs62625044 and may be referred to in studies as 76G>A.

HTR3A gene: This gene codes a subunit of the 5-hydroxytryptamine receptor (serotonin receptor).

Check your genetic data for rs1062613 (23andMe v4, v5; AncestryDNA):

  • T/T: increased risk of IBS-D, increased serotonin receptor function, increased risk of dyspepsia [ref][ref][ref]
  • C/T: somewhat increased risk of IBS-D, increased serotonin receptor function
  • C/C: normal


Bile acid synthesis:

KLB gene: The klotho-B gene is involved in the regulation of bile acid synthesis.[ref]

Check your genetic data for rs17618244 (AncestryDNA only):

  • AA: normal transit time
  • AG: normal transit time
  • GG: (most common genotype) faster colonic transit time in IBS-D[ref]

Enteric nervous system:

There are several TRPV1 variants that have been studied in regards to people’s response to spicy foods (capsaicin). While none of these variants have been researched in relation to IBS, it would make sense that overexpression of TRPV1 genetically would increase the risk of IBS. Check your spicy food genes here. 

The TRPM8 gene has also been implicated in the risk for IBS-Mixed and IBS-C.

Check your genetic data for rs10166942 (23andMe v4, v5; AncestryDNA):

  • C/C: increased risk of IBS-C, slower colonic transit time [ref]
  • C/T: increased risk of IBS-C, slower colonic transit time
  • T/T: normal



Carbohydrates and Enzymes:

If you carry the SI genetic variant that increases the risk of IBS-D, cutting down on the consumption of starches and sucrose is an obvious first step. If you don’t want to cut out carbs altogether, try spacing out your starch/sugar consumption throughout the day. Don’t overwhelm your intestines with a big meal of starches and sugars.  In particular, researchers found that limiting starches, which are converted to maltose, was important.[ref]

There are digestive enzymes available that contain sucrase and maltase. Klaire Labs Vital-Zymes contains both sucrase and maltase and is available on Amazon.

TRP channels (enteric nervous system):

The probiotic VSL#3 has been shown in animals to decrease the number of mast cells (histamine releasers) in the colon and to decrease TRPV1 expression.[ref]  VSL#3 is available online or at your local health food store. It is expensive, but a lot of people swear by it.

Peppermint, which helps some people with IBS symptoms, activates TRPM8.  If you carry the TRPM8 variant (above) – or even if you don’t – give peppermint essential oil or peppermint tea a shot.

Avoiding spicy foods may also help. Capsaicin, which causes the spiciness in hot peppers, can be used to test for hypersensitivity of the TRPV1 channel.  This is done by swallowing a capsule with .75mg of capsaicin and seeing how much symptoms worsen.[ref]


A prescription cannabinoid receptor agonist, dronabinol, has been shown to slow down colonic motility in IBS-D and IBS-Mixed patients.[ref] Currently, dronabinol is only approved by the FDA for chemotherapy and HIV/AIDS patients. If you live in a state where THC is legal, it might be something to consider.

CBD oil binds to the TRPV1 receptor at certain doses. Read more about CBD and your genes.

Diets to try:

Just do a quick google search for more information on any of these that you haven’t heard of before.

The symptoms of gluten intolerance often overlap with IBS. Eliminate gluten-containing foods for a week or two and see if it helps. Then add back in the gluten-containing foods…  see if it makes IBS come back.

A diet that eliminates many of poorly absorbed and easily fermentable foods that your colon bacteria like to munch on (producing gas and painful bloating).

While somewhat extreme sounding, a diet of eating only animal foods (meat, dairy, eggs) is purported by some to cure IBS. It makes sense, in a way, because it would eliminate most fiber that bacteria could eat, thus reducing the painful bloating and gas.

Avoiding Nickel:
People with nickel allergy can be sensitive to foods that contain nickel.  These foods include cocoa, tomatoes, wheat, corn, onions, shellfish, and more[ref]

Low-histamine diet:
This diet reduces histamines in the intestines by eliminating foods high in histamine such as wine, fermented foods, aged meats and cheeses, tomatoes, spinach, chocolate, etc.

Wine Tasting Genes: How your genetic variants influence the way that wine tastes to you

When you think of wine, do you wax poetically about the subtle notes of springtime apple blossoms with hints or truffles — or do you just hope that all your friends can’t tell that you secretly like “Two-Buck Chuck” the best?

If you aren’t a wine lover, you may wonder what all the fuss is about. To be honest, that’s me.

If you asked me what a specific wine tastes like, my usual response is simply ‘umm… wine’.  I don’t get the whole ‘complex notes of black cherry with an earthy plum truffle finish’ thing.

Genetics, of course, explains my indifference towards wine. My histamine-related genes push me towards a headache after drinking it; my frugal gene (yet undiscovered by science) doesn’t let me pay $12 a bottle for grape juice that’s gone bad.

And, as it turns out, my taste receptor gene variants put me squarely in the ‘this wine tastes like… umm…  wine’ category.

Now that all of you wine aficionados are rolling your eyes at my lack of sophisticated palate, let me explain how the taste receptors work and how your genetic variants impact whether you taste certain flavors.

Taste Receptors:

Taste buds on your tongue. Image source: OpenStax Anatomy & Physiology. Creative Commons.

You probably learned in elementary school about taste being one of the five senses. There are five different categories of flavors that you can taste: salty, sweet, bitter, sour, and umami.

Taste buds on your tongue are made up of groups of taste receptor cells. The bumpy surface of your tongue increases the surface area, allowing for lots of taste receptor cells.

Getting more specific

Zooming in on these taste cells, you will find specific taste receptors on the cell membrane. For example, on a taste bud that primarily detects bitter, there will be a lot of bitter taste receptors on the cell membrane of each cell. Activating the receptor with the right molecule causes a signal to be sent to the brain via a nerve.

Taste receptor diagram. Image source: The cell biology of taste. Creative Commons license.

The receptors on the cell membrane of the taste cells are coded for by specific genes. For example, there are 43 different bitter taste receptor genes, all named starting with TAS2R.

The receptor is activated by compounds in the foods that you eat. For example, in broccoli, there is a molecule that fits into and then activates a specific receptor, TAS2R38. That specific receptor only accepts one specific ‘bitter’ molecule – like a lock and key.

You also have specific sweet taste receptors, coded for by the TAS1R family of genes.

Sour, though, is a bit different. Researchers used to think that sour was detected when there were free hydrogen ions available (low pH) and that any of the taste receptors could detect this. More recent research points towards specific potassium channel receptors that are activated at lower pH. [ref]

Tasting wine, activating receptors

Tasting wine – or foods – combines the sensory input of all these different receptors at the same time. You can have different molecules binding to several bitter receptors, activating the sour sense, and also binding to a couple of sweet receptors — all within that same swig of wine.

Bitterness in red wines comes mainly from the polyphenols. Tannins, a type of polyphenol known for astringency, may be present and activate specific bitter receptors.[ref]

The tannins in wine give rise to part of the mouthfeel as well. The astringent taste of tannins produces sensations in the mouth. These sensations are due to the “tightening and shrinking of the oral surface and puckering sensations of the oral cavity”. [ref]

Why does wine taste differently to people?

The taste receptor genes are highly polymorphic — meaning that there are lots of common genetic variants that affect the function of the receptor.

There are forty-three different bitter receptors and multiple sweet receptors. Combine the multiple receptors with variants affecting the function of each receptor to create what your brain receives as the taste.

All these mix together to create very unique individual abilities to taste wines differently.

But why would genetic variants be so common in the taste receptors? Researchers think this gives a population an advantage to have some people who can strongly taste different substances and warn the rest.

Take for example a certain variant in the TAS2R43 gene that causes people to be sensitive to the plant toxins aloin and aristolochic acid. If a few people in a village could taste that substance, they could warn everyone not to eat the plants that contain it. Aloin is a compound in some species of aloe plants that ‘induces bowel movements’ and may be carcinogenic — good that someone in the village can tell you not to eat that type of aloe! About 18% of the population doesn’t even carry a copy of the TASR43 gene. That same taste receptor variant also controls whether the artificial sweetener saccharin tastes bitter to you.[ref]

Let me give you another example. The ability to taste a bitter component of broccoli or Brussels sprouts is mostly due to the TAS2R38 gene. People who cannot taste bitter substances eat more overall servings of vegetables than tasters. The non-tasters can convince the tasters of the benefits of veggie consumption, and the tasters can warn the non-tasters when something is really bitter and possibly toxic.[ref][ref]  While bitter tasters may eat fewer veggies, they may have an advantage in that they also are less likely to drink too much alcohol.[ref]

One way to check for the ability to taste the bitter substances without knowing the TAS2R38 genetic information is to use PROP test strips. This may be something you remember from high school biology labs.  As someone who carries the TAS2R38 variants that make me a non-taster, I can honestly say that those PROP test strips taste like licking a regular sheet of paper…  People who are TAS2R38 tasters claim that the PROP test strips have a bad, bitter aftertaste.

Genes related to wine tasting

Let me get specific about which genetic variants have been researched and found to impact the taste of wine as well as general alcohol (ethanol) consumption.

TAS2R16 (bitter taste gene):

Check your genetic data for rs846664 (23andMe v5; AncestryDNA):

  • AA: normal risk of alcohol dependence
  • AC: normal risk of alcohol dependence
  • CC: altered beta-glycopyranoside tasting, lower risk of alcohol dependence (because alcohol tastes bad) [ref][ref]

TAS2R38 (bitter taste gene):

Check your genetic data for rs1726866 (23andMe v.4 and v.5; AncestryDNA):

  • G/G: Can strongly taste bitter in PROP tests, likely to notice the bitterness in wine, likely to consume less alcohol overall [ref]
  • A/G: Can taste some bitter
  • A/A: Unable to taste bitter in PROP test, likely to think wines taste sweeter[ref], likely to consume more alcohol. [ref]

TAS2R16 (bitter and sour):

Check your genetic data for rs6466849 (23andMe v4 only):

  • TT: wine tastes sourer, decreased tendency to drink wine [ref]
  • CT: wine tastes sourer
  • CC: normal taste perception

TAS1R2 (sweet receptor):

Check your genetic data for rs35874116 (AncestryDNA only):

  • CC: Less likely to drink wine, but if you do drink wine, likely to consume larger amounts [ref]
  • CT: Less likely to drink wine
  • TT: normal

TAS1R3 (sweet and umami receptor):

Check your genetic data for rs307355 (23andMe v5 only):

  • CC: likely to drink more (sweet alcoholic beverages used in study)[ref]
  • CT: likely to drink more (sweet alcoholic beverages used in study)
  • TT:  less likely to drink heavily


Chill it – or not:
Temperature affects the taste sense for about 20-30% of the population. These people are called thermal tasters. So for a portion of the population, the taste of wine may also depend strongly on the temperature of the wine. Try varying the temperature of the wine to see if it makes a difference to you in how it tastes.[article]

Fun stuff:
A few things about taste receptors that I found uniquely interesting: [ref][ref][ref]

  • Taste buds develop in a fetus around the seventh week of gestation.
  • While in the womb, the baby can taste via the amniotic fluid. (Kind of freaky, considering the amount of Taco Bell I ate while pregnant!)
  • Tastes from foods that the mother eats come through in the breast milk.
  • Fancy words: loss of taste is called ageusia and increased taste is called hypergeusia
  • Taste receptors aren’t just located on the taste buds, they can be found in different parts of the body including the skin

Olfactory receptors:
The other half of the equation for wine is how the aroma modifies your taste perception.  There are literally hundreds of olfactory receptor genes, so  I’ll leave that for another article….  But if you want to read a couple of studies on the topic, try this one (odor receptor for the ‘prune note’ in wine?) and this one (grassy smell for white wine?).

The genetics of high triglycerides

Triglycerides are the main type of fat in your blood. Triglyceride is a general term for a type of lipid-containing three fatty acids (tri) bound to a glycerol.  Triglycerides are used by the body as energy. They are also stored in fat cells.

Most of the time when you go to the doctor for a lipids test they are worried about higher LDL or lower HDL levels. These are classically linked to cardiovascular disease risk.  But triglycerides also play a causal role in heart disease.[ref]

People are starting to take note of triglyceride levels as a marker of metabolic syndrome. The defining factors for metabolic syndrome include abdominal obesity, high blood pressure, high blood sugar, low HDL, and high triglycerides.

The immediate response to ‘why do I have high triglycerides’ is to blame the diet and assume you are eating donuts and drinking lots of soda. While diet does play a role (of course), your genetic variants are also very important in basal triglyceride levels.

Digging deeper into triglycerides

Triglycerides – three fatty acids and glycerol – can contain either saturated or unsaturated fatty acids. Most triglycerides contain different types of fatty acids in them.

Saturated fats are carbon-hydrogen chains that have single bonds between all the carbons. Unsaturated fats have either one double bond (monounsaturated) or multiple double bonds (polyunsaturated). The double bonds cause a bend in the molecule, keeping it from packing together as tightly. Thus polyunsaturated fats are usually liquids and saturated fats can be solids at room temperature.

Triglycerides from food cannot be directly absorbed. They are emulsified by lipase, an enzyme secreted by the pancreas to break down fats. In the enterocytes of the small intestines, the fatty acids from triglycerides are packaged into chylomicrons (like a glob of fat). Picture how oil clumps together into droplets when you try to stir it into water.

Chylomicrons contain mostly triglycerides along with a smaller percentage of cholesterol, phospholipids, and proteins. They are secreted into the lymphatic system first, so they don’t go through the liver first like amino acids and sugars.

Testing triglyceride levels:

Testing of triglyceride levels is usually done in a fasted state because the blood levels of triglycerides can rise quite a bit after eating.

Plasma triglyceride tests measure the VLDL and chylomicrons.

Triglyceride level ranges [ref]:

  • Normal: Less than 150 mg/dl
  • Borderline high: 150-199 mg/dl
  • High: 200 – 499 mg/dl
  • Very high: 500 and up

To convert mg/dl triglyceride levels into mmol/L, multiply by .01129.

In studies, hypertriglyceridemia is usually defined as being higher than 150 mg/dl or higher than 2 mmol/L (175mg/dl). About 25% of adults in the US meet this criterion.[ref][ref] Other studies call levels from 150-999 mg/dl mild to moderate hypertriglyceridemia. Levels over 1,000 mg/dl are severe and can cause pancreatitis.[ref]

Disease risk:

High triglycerides are linked to atherosclerosis and stroke. Is this a big increase in risk? That is a hard question to quantify since every study seems to have different endpoints and biases.
Here are some study results:

  • High fasting triglycerides were linked to a 24% increase in the risk of mortality from cardiovascular disease.[ref]
  • All-cause mortality also increases as triglyceride levels increase.[ref – open access]
  • One study states that the slightly elevated triglyceride levels in people with metabolic syndrome or prediabetes are more likely to cause atherosclerosis than the really high levels found in people with genetic mutations [ref – open access]
  • Other studies point to elevated non-fasting triglyceride levels being linked to increased risk of heart attack and death. [ref]

Fructose and high triglycerides:

There have been several studies showing that high fructose intake increases triglycerides. This may lead you to assume that drinking the periodic soda is causing your high triglycerides…

The animal studies pretty clearly show that fructose increases triglyceride levels. In rats, replacing water with fructose water increases blood pressure, liver fat, and triglycerides pretty significantly. [ref] [ref]

Human studies on fructose and triglycerides show similar trends, but much less dramatic results.

A study using normal weight adults looked at the difference between consuming 150g/d of fructose or 150 g/day of glucose for 4 weeks.  They did this by substituting the fructose or glucose for other calories in the diet, so overall calories weren’t affected. After 4 weeks, there was no increase in visceral fat, muscle fat, or liver fat and no changes to blood pressure. In fact, the only change after 4 weeks was that triglycerides in the fructose group went up by 35 mg/dl (still in the normal range, though). There was no change in triglycerides in the glucose group.[ref]

Studies in humans where fructose is added on top of their normal caloric intake do show a larger increase in triglyceride. One study that added fructose for a 35% increase in calories showed triglyceride levels rising 75%.[ref] But it is hard to differentiate between suddenly adding that many calories vs. those calories being from fructose. [ref]

A meta-analysis of a bunch of studies concluded there is no difference on triglyceride levels from fructose vs sucrose vs glucose.[ref]

Triglycerides, leptin, and obesity:

Leptin is the hormone that signals to the brain that you are full and don’t need to eat.  In people who are overweight or obese, there is usually a high level of leptin, but that signal isn’t being received in the brain (leptin resistance). The question is ‘why’…  One theory is that elevated triglyceride levels interact with leptin in the brain, causing the leptin resistance.

Triglyceride levels rise when you are in a state of starvation as your body activates fat from adipose tissue. A recent study recently looked at the connection between triglyceride levels and leptin resistance. The study found that triglycerides do cross the blood-brain barrier and can induce leptin resistance. [ref – open access]

Theoretically, it makes sense that in times of starvation, high triglycerides would block the leptin signal, driving people to need more food. But in our modern epidemic of metabolic syndrome and high triglyceride levels, this is causing leptin resistance and increasing the desire to eat even when overweight.

HDL and triglyceride levels:

High triglyceride levels usually correspond to lower HDL levels.  This is part of what makes research on cardiovascular disease risk and triglycerides difficult — is it the low HDL or high triglycerides that cause the increase in risk? [ref – open access]

Genetic variants that increase triglyceride levels:

Below are some of the more common (found in >1% of the population) genetic variants that affect triglyceride levels. Most studies now point to the interaction between these variants. For example, if you carry a couple of the variants that raise your triglyceride levels, it may be causing your high triglycerides. But carrying a couple of the variants that lower your triglycerides along with one that raises it could give you a normal triglyceride level (depending on diet).

What is missing from this list is the rare mutations that cause hypertriglyceridemia.

APOA5 gene:

The APOA5 gene codes for apolipoprotein A5, which is a lipoprotein that is involved in triglyceride levels, possibly through activating lipoprotein lipase (LPL).

Check your genetic data for rs662799 (23andMe v4, v5; AncestryDNA):

  • A/A: normal
  • A/G: increased triglyceride levels, 16% increase in triglyceride levels [ref]
  • G/G: increased triglyceride levels[ref][ref][ref], 32% increase in triglyceride levels[ref]

Check your genetic data for rs2075291 G185C (23andMe v4; AncestryDNA):

  • G/G: normal
  • G/T: high triglyceride levels, especially in Asian populations [ref][ref][ref]
  • T/T: very high triglycerides, especially in Asian populations.

Check your genetic data for rs3135506 (23andMe v4, v5; AncestryDNA):

  • G/G: normal
  • C/G: increased triglyceride levels
  • C/C: increased triglyceride levels[ref][ref]

Check your genetic data for rs651821 (23andMe v4, v5; AncestryDNA):

  • C/C: normal
  • C/T: increased triglyceride levels
  • T/T: increased triglyceride levels[ref][ref][ref]

LPL gene:

The lipoprotein lipase (LPL) enzyme releases fatty acids to be used as fuel. It does this by hydrolyzing the triglycerides in plasma lipoproteins. Genetic variants that decrease this enzyme can raise triglyceride levels.

Check your genetic data for rs328 (23andMe v4, v5; AncestryDNA):

  • C/C: normal
  • C/G: lower triglycerides
  • G/G: lower triglycerides [ref][ref]

Check your genetic data for rs320 (23andMe v4, v5):

  • T/T: normal
  • G/T: slightly lower triglycerides
  • G/G: slightly lower triglyceride [ref][ref]

Check your genetic data for rs268 (23andMe v4, v5; AncestryDNA):

  • A/A: normal
  • A/G: higher triglycerides
  • G/G: higher triglycerides [ref]

GCKR gene

Glucokinase regulatory protein regulates glucose kinase, a sensor that regulates glucose from glycolysis.

Check your genetic data for rs780094 (23andMe v4, v5; AncestryDNA):

  • C/C: normal
  • C/T: slightly higher triglycerides [ref]
  • T/T: higher triglycerides [ref][ref] but possibly no increase in heart disease risk[ref]

APOE gene:

The APOE E4 variant is also tied to a risk of increased triglyceride levels.  If you want to know your APOE status, read through the article on Alzheimer’s disease and APOE. 

What are we missing here?  Rare mutations…  

Here are a few that are covered in 23andMe or AncestryDNA.  But this is just the tip of the iceberg for rare variants that could have a large impact on high triglycerides. What does ‘rare’ mean — usually that the mutation is found in less than 1 in 1000 people.

Check your genetic data for rs5126 (23andMe v5 only):

  • A/A: normal
  • A/C: carrier of pathogenic APOC2 variant
  • C/C: 2 copies of pathogenic APOC2 variant[ref][ref]

Check your genetic data for rs120074114 (AncestryDNA only):

  • A/A: normal
  • A/C: carrier of pathogenic APOC2 variant
  • C/C: 2 copies of pathogenic APOC2 variant[ref][ref]

Check your genetic data for rs199673455 (23andMe v5 only):

  • G/G: normal
  • A/G: carrier of pathogenic mutation for transient hypertriglyceridemia
  • A/A: 2 copies of pathogenic mutation for transient hypertriglyceridemia [ref]



If you have high triglycerides, carrying some of the variants (above) that raise your triglyceride levels is part of the problem. The other half of the equation is diet and lifestyle.

It is pretty clear that high fructose corn syrup increases triglyceride levels. So cut out the soda or switch to drinks without high fructose corn syrup.

A ketogenic diet was shown in a (small) study to reduce triglyceride levels fairly significantly. [ref]

The Mediterranean diet was shown in a trial to reduce triglycerides (a little). [ref]

Omega 3s:
There are prescription formulations of omega-3 fatty acids that are prescribed for high triglycerides. They have been shown in several trials to reduce triglyceride levels and VLDL levels.[ref]

An obvious alternative to prescription omega-3s is to take fish oil supplements or eat more fish. This has been shown in studies to reduce high triglycerides in people with non-alcoholic fatty liver disease.[ref] [ref]

In rat studies, resveratrol prevents the rise in triglycerides due to fructose supplementation. [ref] Human studies on non-alcoholic fatty liver disease show mixed (or little) benefit from resveratrol on triglycerides.[ref]

Betaine and choline:
Betaine and/or choline may influence triglyceride levels. Betaine is shown to be higher in people with lower triglyceride levels.[ref]

A mouse study showed that adding betaine to the diet of APOE deficient mice caused triglycerides to go down.[ref]

Niacin has long been recommended as a way to decrease cardiovascular disease risk. Study results, though, are kind of all over the place as far as how much niacin really helps when looking at mortality rates from heart attacks.[ref]  Studies do show that niacin supplementation reduces triglyceride levels for most, but the long term effects on liver function warrants caution.[ref][ref]

l-carnitine supplements have been shown in animal studies to reduce triglyceride levels.[ref]


Genetic links to infertility for women.

The statistics on infertility are astounding. The CDC estimates that 12% of women overall in the US have impaired fertility. For women over age 30, that statistic rises to 25%! [ref][ref]

Some of the causes of infertility for women can be categorized as follows:

  • hormonal issues:  thyroid problems, PCOS, HPA axis dysregulation, reproductive hormone dysregulation
  • structural issues: fibroids, blocked fallopian tubes, other structural abnormalities
  • ovarian insufficiency or premature menopause
  • recurrent miscarriages
  • and more

This article highlights some of the common genetic variants that may play a role in infertility. It is just a starting point… My hope is that it gives you enough information to get started on figuring out the root cause of your problems conceiving.

Everything here is for informational purposes only, based on research studies on genetics and fertility. Please talk with your doctor for medical advice or seek help from a fertility coach or expert. 

A crash course in reproduction:

A lot of people think of pregnancy in basic terms: sperm meets egg and 9 months later you have a baby.  Birds do it, bees do it.  Heck, even trees do it, in their own way.

But when you get down to the specific details, it gets a lot more complicated.

At puberty, women have around 300,000 to 400,000 follicles in their ovaries. These primordial follicles are tiny fluid-filled sacs that contain the oocyte (immature egg cell). Over the course of a woman’s reproductive years, only 400 – 500 eggs will reach maturity.

Hormones stimulate the development of some of the follicles each month. Usually only one will reach maturity each month, at which point ovulation occurs.  (The other follicles are broken down and reabsorbed.)

That egg cell that gets released at ovulation is what can get fertilized by the sperm, resulting in pregnancy if all goes well. The egg needs to be healthy with no DNA damage.

For all of this to happen, the reproductive hormones need to be at the right levels and at the right time. Follicle stimulating hormone (FSH) rises at the right time to stimulate the immature follicles to begin to mature. Without FSH, the immature follicles will go through apoptosis (cell death).

When the follicle reaches a certain size, it will start secreting estrogen. This causes a surge in gonadotrophin-releasing hormone (GnRH).

The surge in GnRH causes a surge in luteinizing hormone (LH) secretion, which triggers ovulation.

As women age, they have fewer follicles in their ovaries eventually reaching the end of reproductive span at menopause. A hormone called AMH (anti-mullerian hormone) is often used as a marker of ‘ovarian reserve’, an estimate of available eggs.

But the ovaries aren’t like a gumball machine, spitting out good gumballs (eggs) up until the last one comes out. Oxidative damage, insults to the cells, etc. cause egg quality to decline as we age.

Conditions that can decrease fertility rates include PCOS (polycystic ovarian syndrome), hypothyroidism, diabetes, and autoimmune diseases.

The risk of recurrent miscarriages also increases with age. Blood clots can increase the risk of recurrent miscarriages, and several genetic variants cause increased clotting.

Genetic variants and pathways that impact fertility:

How does the MTHFR variant impact fertility for women?

The MTHFR gene codes for a key enzyme in the methylation cycle. It is the final step for converting folate into the form the body uses, methylfolate.  While most women know that folate is important to a growing baby, the MTHFR gene can also impact other aspects of fertility.

Research shows that the MTHFR C677T and A1298C variants impact fertility in a couple of specific ways.

Carriers of two copies of the C677T variant have altered reproductive hormone levels (FSH and AMH) that impact egg number and quality. This can also alter the hormone amount needed during IVF. [ref][ref][ref]

Carrying two copies of the C677T and/or A1298C variants are linked to a higher risk of recurrent miscarriages in many (but not all) studies.[ref] [ref][ref][ref]

Check your genetic data for rs1801133  (23andMe v4, v5; AncestryDNA):

  • G/G: normal (wildtype)
  • A/G: one copy of MTHFR C677T allele (heterozygous), MTHFR enzyme efficiency reduced by 40%
  • A/A: two copies of MTHFR C677T (homozygous), MTHFR efficiency reduced by 70 – 80%

Check your genetic data for rs1801131 (23andMe v4, v5; AncestryDNA):

  • T/T: normal (wildtype)
  • G/T: one copy of A1298C allele (heterozygous), MTHFR enzyme efficiency slightly reduced
  • G/G: two copies of A1298C (homozygous), MTHFR efficiency reduced

Blood clot disorders and miscarriage risk:

There are several genetic variants that increase the risk of blood clots and conditions such as deep vein thrombosis. These genetic variants also increase the risk of recurrent miscarriages due to clotting. This does NOT mean that everyone who carries these variants will have a miscarriage. It is something to talk with your doctor or fertility specialist about.

Note that the 23andMe and AncestryDNA raw data is marketed for informational purposes, not clinical testing. So if your raw data shows that you carry one of the risk factors below, you should talk with your doctor and consider possibly getting a second test done for verification before making medical decisions.

Factor V Leiden (read more here):

Check your genetic data for rs6025 (23andMe v4, v5; AncestryDNA):

  • C/C: normal
  • C/T: one copy of factor V Leiden, increased risk of miscarriage [ref][ref]
  • T/T: two copies of factor V Leiden, increased risk of miscarriage [ref][ref]

Prothrombin G20210A variant (read more here):

Check your 23andMe data for i3002432 (rs1799963, G20210A):

  • A/A: increased risk of blood clots, stroke; increased miscarriage risk [ref][ref][ref]
  • A/G: increased risk of blood clots; increased miscarriage risk
  • G/G: normal

PCOS and fertility:

PCOS (polycystic ovary syndrome) can also make it harder for some women to conceive. Women with PCOS can have anovulatory or irregular menstrual cycles as well as hormonal dysregulation. [ref][ref]

PCOS is thought to be partially genetic, with about 70% of the disease risk due to genetic factors.

There are quite a few genes that contribute to the risk of PCOS. Instead of listing them all here, please read my article on PCOS.

Optimizing for fertility:

Your overall health impacts your ability to reproduce. This makes sense for all animals and especially for humans.

There are quite a few genetic variants that affect very basic aspects of health that also affect fertility. You need healthy egg cells in order to get pregnant. This list is a bit of a hodge-podge of some of those variants that affect the quality of the oocyte.[ref]


The ‘sleep hormone’ does a lot in the body. Within cells, it acts as a natural antioxidant, reducing reactive oxygen species. Melatonin receptors are found in high levels in the ovaries and in the follicle cells. Melatonin turns out to be fairly important in egg quality for IVF. [ref][ref][ref][ref] Melatonin also may play a role in keeping the mother’s body from rejecting the fetus.[ref]

How can you increase melatonin? Two free things you can do that will greatly impact melatonin levels: Block blue light at night, get out in the sunshine during the day.

Below is one common melatonin receptor variant that increases the risk for PCOS. Read more about other melatonin genetic variants here.

Check your genetic data for rs10830963 ( 23andMe v.4, v.5; AncestryDNA):

  • G/G: linked to higher risk of diabetes, increased fasting glucose, PCOS [ref][ref]
  • C/G: linked to higher risk of diabetes, increased fasting glucose
  • C/C: normal
Vitamin A:
Active forms of vitamin A in the body are essential for both male and female reproduction.[ref]

Vitamin A can be obtained in the diet in retinol forms from animals sources or in beta-carotene in plants.  The beta-carotene form has to be converted by the body into the retinol form — which is where genetics comes into play.

Note that while essential in the right amount, too much vitamin A, through drugs like Accutane (isotretinoin, acne medicine) or through really high levels of vitamin A supplements, can cause birth defects.

The BCMO1 enzyme converts beta-carotene into the retinal form the body uses. There are two gene variations in the BCMO1 gene that help determine a person’s ability to convert beta-carotene into the retinol a body uses. [ref]

People with a T allele on both rs12934922 and rs7501331 have a 69% decreased conversion of beta-carotene to retinol.

Check your genetic data for rs7501331 (23andMe v.4 and v.5, AncestryDNA):

  • C/C: normal
  • C/T: decreased beta-carotene conversion by 32%
  • T/T: decreased beta-carotene conversion by 32% or more

Check your genetic data for rs12934922 (23andMe v.4 and v.5):

  • A/A: normal
  • A/T: decreased beta-carotene conversion
  • T/T: decreased beta-carotene conversion

Detoxification pathways:

BPA and phthalates are two well known endocrine disruptors that are extremely prevalent in our environment today.  BPA is well known as a component of plastics, but it is also found in food can linings, processed foods, thermal receipt paper, and more. Phthalates are found in fragrances (laundry detergent, air fresheners), lotions, plastics, pharmaceuticals, nail polish, and more. [ref] [ref]

Both BPA and phthalates have been clearly shown in animal studies to disrupt reproduction in multiple ways. They also may be affecting the reproduction of offspring.[ref]

In women undergoing IVF, increasing concentrations of BPA in their blood correlates linearly with decreasing number of oocytes and pregnancy.[ref] And yes, nearly everyone has BPA and phthalate metabolites in their body.

Some people can detoxify and clear out the BPA and phthalates better than other people.

Read more about the genetic variants associated with BPA detoxification.

Read more about the genetic variants associated with phthalate detoxification.


I’ve thrown a lot of information into this article, but it is just a portion of what goes into the mix for fertility.

If you are dealing with infertility, genetic variants are probably playing a role — whether through PCOS, altering your vitamin or hormone levels, or through increasing the risk for problems from toxins.  But this is just a part of the picture…  stress, sleep, and diet are all important also.

Getting help:
Obviously, the first place to go for help when trying to conceive is your OB/GYN for testing. Your OB can do ultrasounds and other tests to rule out a physical cause. Hormone testing is also available to make sure  everything is normal there.

There are also fertility experts that offer online coaching and help as you go through this process. Julie Chang at Fertility Eggspurt is one that I can recommend if you are looking for information online.  Or ask around for recommendations in your local area. Talking with people, getting lots of good information, and getting some emotional support are all helpful when dealing with problems trying to conceive.

MTHFR for fertility:
There is a lot of information available about MTHFR and taking methylfolate instead of folic acid. Here is my take on folic acid along with the research on it.

It is vital for women who carry the MTHFR variants to ensure that they meet their body’s needs for the methylation cycle. This can include adding more folate to the diet (liver, green leafy veggies, legumes) or taking a methylfolate supplement.

But there are other ways of supporting methylation also. This includes getting plenty of choline, glycine, and creatine.[ref][ref]

In general, a balanced diet that includes eggs (choline), organ meats (creatine, choline, folate), organic vegetables (folate), and bone broth (glycine) may cover your dietary needs for methylation cycle optimization. If you are on a diet that cuts out any major food groups, you should track your diet for a week or two to make sure you are not missing out on anything.

I’m going to mention sleep one more time as being important since I think it is undervalued in health and fertility. Melatonin is important, but that is only one aspect.  There are a lot of recent studies that point to circadian rhythm and sleep as being very important in reproduction (both animal studies and human studies). A 2018 study found that sleep disorders (non-sleep apnea related) increased the risk of infertility by 3 to 5 fold.[ref] [ref][ref][ref]

There have been quite a few studies on the effects of eating more fruits and vegetables on IVF outcomes.

Some studies show that increasing amounts of fruit and veggies don’t make much difference. What does make a difference for oocyte quality and IVF outcome is avoiding pesticide residue. This could mean eating organic fruits and vegetables (or just avoiding conventional produce).[ref]  I was surprised that more fruits and vegetables didn’t make a difference in fertility, but this may be due to women taking prenatal vitamins have the micronutrients covered fairly well. [ref][ref]

Other studies, though, in women trying to conceive, do show that increasing fruit consumption decreases the time to conception — and that higher fast food consumption increases the time to conception. But the effect size is fairly small here. The changes were on the scale of 0.3 to 0.9 months difference — so less than a month difference in time to conception.


Should you take folic acid?

There is a lot of buzz online about MTHFR variants and the need to avoid folic acid. I’ve seen recommendations ranging from avoiding all processed foods that are fortified with folic acid — to recommendations that people with MTHFR variants need to take extra folic acid.

I’ve dug into the topic to see what is in the research studies about folic acid. Is it so evil that everyone should go out of their way to avoid it? Or is it a wonderful benefit for women trying to conceive?

What is folic acid?

Folic acid is a synthetic form of folate (vitamin B9) that is temperature and pH stable, allowing it to easily be added to processed foods and multivitamins.  The chemical name for folic acid is pteroylmonoglutamic acid or PteGlu.

Natural folates from foods differ a bit from synthetic folic acid. They contain more than one glutamic acid and are called pteroyl polyglutamic acid. They are less heat stable and cooking or processing can decrease the amount of natural folate in foods.[ref]

The body converts folates (folic acid and natural folates from plants) into tetrahydrofolate. This conversion is a little different for natural folate vs. folic acid.

A 2014 review in Preventive Nutrition and Food Science explained the breakdown of folic acid:

  • First folic acid must be reduced to dihydrofolate (using the DHFR enzyme).
  • Then the DHFR enzyme is needed again for the conversion of dihydrofolate into tetrahydrofolate (the active version used by the body).

Tetrahydrofolate is then used (along with the MTHFR enzyme) for a critical step within the methylation pathway. This vital pathway is responsible for methyl groups that are needed in DNA synthesis, detoxification reactions, the creation of certain neurotransmitters, and more.

How is folic acid different from methylfolate?

While folic acid has to go through a couple of reactions to become the active form of folate used by the body, methylfolate (L-5-methyltetrahydrofolate) skips all those steps and can be used immediately.  Methylfolate is available in supplemental forms; it isn’t added to fortified foods, in part, because it is quite a bit more expensive than folic acid.

What happens to folic acid that isn’t used by the body?

Often when reading about folic acid you will see mentioned that it is a water-soluble vitamin that isn’t toxic.  This may lead some to assume that extra folic acid won’t hurt you. But this may not be a correct assumption.

The folic acid that isn’t used by the body can often be found in the bloodstream as unmetabolized folic acid. There are concerns that the excess folic acid could inhibit the DHFR enzyme from converting dihydrofolate into tetrahydrofolate when the body is needing it. Both reactions use the DHFR enzyme, but most of the time the enzyme is preferentially used for creating the active form (tetrahydrofolate) when needed. Some studies indicate that too much unmetabolized folic acid, though, inhibits DHFR from completing that second reaction. This could leave cells lacking in tetrahydrofolate when high levels of folic acid are in circulation.[ref]

There are also concerns that excess folic acid intake could downregulate folate transporters in the kidneys and intestines. [ref]

How much folic acid does it take to get unmetabolized folic acid in the bloodstream? 

  • One study shows that the level is around 400μg for the average adult. [ref]
  • Another study was completed in the UK, which had not mandated fortification of flour, so the participants had no unmetabolized folic acid in their bloodstream prior to beginning the study.  The study found that around 200 μg doses would show up in the bloodstream. The timing was also important and repeated exposures close together had a cumulative effect.[ref]
  • Finally, a 2012 study looking at the effects of supplementing with either 1.1mg or 5 mg of folic acid found that there is a great variation in people’s capacity for metabolizing folic acid.[ref]

How much folic acid are people eating?

In the US, flour is fortified at 140 mcg/100g.  But since I have no idea how many grams of flour are in most foods, let’s take a look at servings of some popular foods [ref]:

  • A bowl of cheerios gives you 50% of the daily value for folic acid (200mcg?) [website]
  • Two slices of bread for a sandwich gives you 70 mcg.
  • A bagel contains 119 mcg.
  • 1 cup of macaroni gives you 179 mcg.
  • 1 cup of enriched white rice gives you 200 mcg.

This is just folic acid — many foods contain natural folate as well.

A study of over 2,700 US children, adolescents, and adults found that unmetabolized folic acid was found in almost all blood samples.  [ref]

Does folic acid cause cancer?

This is a question that researchers have been looking into for a few decades. It’s a controversial topic without totally clear answers.

It has been theorized that mandated folic acid fortification in 1998 caused an increase in the number of colon cancer cases in the US. The sharp increase in colon cancers from 1998-2002 came after a long period when colon cancer rates had been declining. [article] [ref]

Recent studies have shown that folic acid in higher amounts, such as 1mg/day, are linked to breast cancer, prostate cancer, and colon cancer. [ref]

High amounts of unmetabolized folic acid are also associated with decreased natural killer cells (a cytokine that is part of the body’s defense against cancer).[ref]

One commonly used cancer-fighting drug is methotrexate, which blocks the action of an enzyme (DHFR) that is part of the folate pathway. This essentially inhibits the synthesis of DNA, RNA, and more in cancer cells — and healthy cells.

Here are a few of the studies on cancer and folic acid:

  • A study of 848 women with breast cancer and a control group of 28,345 women without cancer found that premenopausal women with higher plasma folate level were at a higher risk of breast cancer. The study was conducted to determine if B12 and folate prevented breast cancers; researchers noted that the results were ‘unexpected’. [ref]
  • Another study found that women who had higher plasma folate levels (top third) were at double the odds of ERβ− breast cancer.[ref]
  • An animal study investigated folic acid’s effect on breast cancer. Animals with mammary tumors received a diet containing higher amounts of folic acid (2.5 to 5 times the recommended amount) for 12 weeks.  Compared with the animals fed a control diet, the folic acid fed animals had significantly larger tumors. [ref]
  • A 2009 randomized placebo-controlled trial for colorectal adenomas found that folic acid supplementation (1 mg/day) more than doubled the risk of prostate cancer.  “Among the 643 men who were randomly assigned to placebo or supplementation with folic acid, the estimated probability of being diagnosed with prostate cancer over a 10-year period was 9.7% (95% confidence interval [CI] = 6.5% to 14.5%) in the folic acid group and 3.3% (95% CI = 1.7% to 6.4%) in the placebo group ” [ref]

Don’t freak out just stop eating folate all together...  folate in the right amounts has been repeatedly shown to reduce the risk of getting cancer. The key here seems to be that adding folic acid when there is cancer already present will increase the growth of cancer.

Does folic acid cause autism?

This is another controversial topic without a clear answer.

A meta-analysis that combined together data from a bunch of studies showed that the overall effect of supplementing with folic acid while pregnant is that it reduces the risk of autism.[ref]

Other studies, though, raise some serious questions about folic acid on an individual level. A study of 1,391 mothers in Boston found that high maternal folate and/or B12 levels significantly increased the risk of autism in their children. Overall, though, women who used multivitamins were at a lower risk. The researchers did factor in MTHFR genetic variants and found that they were not a risk factor. [ref]

Mouse studies also raise questions about the impact of higher levels of folic acid during pregnancy. The results showed that high folic acid during pregnancy leads the offspring to have disturbed choline/methyl metabolism, memory impairment, and embryonic growth delays.  [ref]

History of how Folic Acid came to be supplemented in the US

Widespread folic acid fortification began in the US in 1996 and then became mandatory in 1998. It is currently added to all “enriched bread, flour, cornmeal, rice, pasta, and other grain products”. [ref]  This mandate was made to reduce the risk of neural tube defects, which happened at the rate of  2,500 babies with NTD/year in the US in 1992. A 2015 CDC article claims: “The birth prevalence of NTDs (proportion of babies in the population born with an NTD) has decreased by 35% in the United States since folic acid fortification was required in 1998.”   [ref]

The history of the FDA decision to mandate fortification with folic acid is interesting to read.  It states that:
Folic acid fortification, for all practical purposes, was not even on the regulatory horizon when it was first included in the 1990 Nutrition Labeling and Education Act (NLEA). FDA scientists at the time felt that the charge to consider the link between folic acid and neural tube defects literally came “out of the blue.” Later, they concluded it probably started with a science workshop hosted by CDC in the late 80s in which unpublished data on folic acid and neural tube defects were presented and seized upon by the supplement industry.” The article goes on to explain that a British study published in 1991 showed that women who already had a child with neural tube defects reduced their risk of having a second child with NDT when they supplemented with 4 mg of folic acid per day. This study was in contrast to the FDA contracted report in 1991 which stated that studies had failed to show the connection between folic acid and NTD.

By August of 1992, the FDA changed its stance on folic acid.  The article goes on to say:

“In August and September 1992, FDA reviewed results obtained from two additional, unpublished studies, and worked closely with authors and journals publishing them to ensure that the results were made public early. The first, a Hungarian research study, showed a reduced risk of ntd’s in women consuming .8 mg. of folic acid as part of a multivitamin/mineral supplement. The study had been conducted with a sample of women in the general population without a previous history of an ntd pregnancy. The second study was a case control study of women in the general population of Boston, Toronto, and Philadelphia and was referred to as the “Werler study.” This study suggested that .4 mg. of folic acid daily from multivitamin/mineral supplements was associated with a reduced risk of ntd. It also suggested that a diet adequate in folate with more than .25 mg. daily was protective. The new preponderance of scientific evidence on folic acid created a platform from which the Public Health Service (PHS) spoke on September 14, 1992. PHS formally recognized the link between folic acid intake and ntd’s as a compelling public health issue. It recommended that all women of childbearing age should have adequate folate intakes (.4 mg. daily) throughout their childbearing years, but warned that the total intakes should not exceed 1 mg.”

The Werler study that the FDA used for their recommendation looked at 436 cases of NTD with a control group of 2,615 babies that had other types of birth defects. They based the conclusion on the reported use of daily multivitamins that also contained folic acid. I admit that I am confused by this study, specifically by why the control group was only babies with birth defects and how the conclusion was reached that it was the folic acid in the multivitamin that lowered the risk of NTD.

Please don’t get me wrong…  I am not really questioning a link between NTD and folate levels since there is other evidence for this. The CDC estimates that folic acid fortification in the US prevents 1,300+ cases of NTD each year.[ref]  (You can decide if it is a good trade-off for possibly increased cancer risk.)

Rather, I’m surprised at how little data the FDA used in making the decision to force the fortification of folic acid on the public. I had rather naively assumed that there were lots of good studies showing without a doubt that 400 μg/d  of folic acid was exactly what we all needed.

Genetic Variants Related to Folic Acid Metabolism

DHFR – Dihydrofolate reductase

The DHFR gene codes for the enzyme that converts dihydrofolate (from folic acid or folate) into tetrahydrofolate. It also converts folic acid into dihydrofolate.

Check your genetic data for rs70991108: (23andMe v5 only):

  • I/I orTGGCGCGTCCCGCCCAGGT: normal DHFR variant
  • D/I: carrier of one copy of a deletion in part of the DHFR gene
  • D/D or -/-: carrier of two copies of a deletion in part of the DHFR gene, more unmetabolized folic acid[ref]

The 19bp deletion is quite common and found in almost half the population. Studies are mixed as to the effect of the deletion:[ref]

  • One study showed that people with two copies of the deletion were twice as likely to have unmetabolized folic acid when intake was over 500mcg/day.[ref]
  • The deletion is also linked to an increased risk of breast cancer in multivitamin users[ref], which may point to it having an effect with higher folic acid supplementation.
  • In the elderly, those with two copies of the deletion and higher folate levels had significantly worse memory score[ref], which again points to a detrimental effect from folic acid for those with the deletion.

Check your genetic data for rs1677693 (23andMe v4; AncestryDNA):

  • T/T: decreased risk of colon cancer only for people not taking folic acid supplements[ref]
  • G/T: decreased risk of colon cancer only for people not taking folic acid supplements
  • G/G: normal (most common)

The study referenced above looked at colon cancer cases in the US, Canada, and Australia. The rs1677693 T-allele was associated with a decreased risk of colon cancer — but only in people not taking vitamins with folic acid in them. But note that these people were probably all getting some folic acid through fortified foods.

Check your genetic data for rs1643649 (23andMe v4 only): (the minor allele is C)

  • A study showed the minor allele increased susceptibility to spina bifida.  [ref]

Check your genetic data for rs1650697 (23andMe v4, v5; AncestryDNA):

  • A/A: alters the effect of methotrexate on psoriatic arthritis[ref] decreased DHFR expression [ref] likely to live longer when being treated for lung cancer[ref]
  • A/G: alters the effect of methotrexate on psoriatic arthritis[ref] decreased DHFR expression
  • G/G: more common variant

MTHFR is a well researched genetic variant in the folate pathway. It converts tetrahydrofolate into methyltetrahydrofolate for use in the methylation cycle.

Check your genetic data for rs1801133  (23andMe v4, v5; AncestryDNA):

  • G/G: normal (wildtype)
  • A/G: one copy of C677T allele (heterozygous), MTHFR efficiency reduced by 40%
  • A/A: two copies of C677T (homozygous), MTHFR efficiency reduced by 70 – 80%

Check your genetic data for rs1801131 (23andMe v4, v5: AncestryDNA):

  • T/T: normal (wildtype)
  • G/T: one copy of A1298C allele (heterozygous), MTHFR efficiency slightly reduced
  • G/G: two copies of A1298C (homozygous), MTHFR efficiency reduced

Read more about the MTHFR variants

While at first glance it may seem that those with MTHFR 677 and 1298 variants may gain some kind of benefit from folic acid as long as their DHFR gene is working well, this may not be the case. The studies on high levels of unmetabolized folic acid decreasing the conversion to tetrahydrofolate would indicate that people with MTHFR variants would be at an increased risk for not having enough active folate for the methylation cycle.

Another recent study showed that, regardless of MTHFR status, [6S]-5-MTHF (methyl folate) had higher bioavailability than folic acid.[ref]


I’m not a doctor, so don’t take this as medical advice… Instead, this is a suggestion for a common sense application of the research. 

Figure out how much folic acid you get in a day:
I think that caution is warranted for higher doses of folic acid, especially in older people or anyone at a higher risk for cancer.

The question is whether a “higher dose” is 200 mcg or 400 mcg since the studies referenced above showed different answers for the point at which unmetabolized folic acid is found.  My guess is that for anyone with a DHFR variant that is on the lower side.

Check your multivitamins, prepackaged shakes, vitamin drinks, etc to see how much you are getting.

Should everyone stop eating foods fortified with folic acid?
Not necessarily. You can drive yourself a bit nuts trying to eliminate this or that from your diet.  But I think people need to realize how much folic acid they are getting in fortified foods and how that can stack up over a day. Try tracking your intake for a week to see how much folic acid you consume. If you are consuming more than you should, then switch out some of the higher foods in your diet, such as white rice or cereal, for options that don’t have folic acid added. You can find unfortified rice in some of the imported varieties, such as imported Indian basmati rice.

What about prenatal vitamins?
The research is pretty clear that women trying to conceive and during the first trimester need plenty of folate, but this doesn’t mean that folic acid is your only option. There are many options now for prenatal vitamins with methylfolate rather than folic acid.

What about MTHFR?
Limiting folic acid consumption to be less than the level for unmetabolized folic acid seems prudent for anyone with an MTHFR variant. If you don’t get enough folate through your diet, methylfolate is a better option for supplementation than folic acid.

Foods high in folate:
Including foods that are high in natural folate is important for overall health. Higher folate foods include legumes, green leafy vegetables, asparagus, avocado, and liver. Stacking a few of those together in your diet can provide the 400 mcg of folate recommended each day — without needing to add foods fortified with folic acid.



Article originally published in June 2016. Updated and republished in April 2019. 

How do your genes influence your vitamin B12 levels?

Vitamin B12 is essential for your health! It is a cofactor for biological reactions such as creating the myelin sheath in nerve cells and the synthesis of DNA (rather important!). A lack of vitamin B12 (also known as cobalamin) can create a cascade of effects. [ref]

There are several genes that can influence your absorption, transport, and need for vitamin B12.  Some people need higher amounts of B12, and some people thrive on different forms of B12. Looking at your genetic data may help you figure out what is going on in your body.

Background Info on Vitamin B12

Vitamin B12 as a supplement can be found in four different forms: cyanocobalamin, methylcobalamin, adenosylcobalamin, and hydroxocobalamin.  The cyanocobalamin form is often found in cheaper vitamins and added to processed foods. It must be converted by the body before use.  The methylcobalamin and adenosylcobalamin are active forms used by the body.

Vitamin B12 deficiency or insufficiency has been shown to cause:[ref]

  • mental confusion
  • tingling and numbness in the feet and hands
  • memory loss
  • disorientation
  • megaloblastic anemia
  • gastrointestinal symptoms

To be able to absorb B12 from foods, you need to have adequate intrinsic factor produced in the stomach. This is something that is often depleted in the elderly, leading to B12 deficiency.

Genetic variants that influence vitamin B12:

These genetic variants don’t usually cause frank vitamin B12 deficiency on their own. Instead, they decrease or alter the use and availability of it in the body. So these variants are more about optimizing B12 status rather than overcoming a disease state.

MTRR gene:

This gene codes for methyltransferase reductase, an enzyme that is involved in using methylcobalamin (methyl B12) in the methylation cycle. Without sufficient B12, homocysteine levels can increase.

Check your genetic data for rs1801394 A66G (23andMe v4, v5; AncestryDNA):

  • AA: normal
  • AG: decreased enzyme activity, increased homocysteine levels
  • GG: decreased enzyme activity, increased homocysteine levels[ref]

MTHFR gene:

The MTHFR gene codes for an enzyme that converts folate into the active form, methyl folate, that the body uses. This methylation pathway is also dependent on B12.

Check your genetic data for rs1801133 C677T (23andMe v4, v5; AncestryDNA):

  • G/G: normal (wildtype)
  • A/G: one copy of C677T allele (heterozygous), MTHFR efficiency reduced by 40%, associated with increased homocysteine and lower B12 levels
  • A/A: two copies of C677T (homozygous), MTHFR efficiency reduced by 70 – 80%, associated with increased homocysteine and lower B12 levels[ref][ref]

TCN1 gene:

This gene codes for a transporter for vitamin B12.

Check your genetic data for rs526934 (23andMe v4,v5; AncestryDNA):

  • AA: normal
  • AG: lower circulating vitamin B12 levels
  • GG: lower circulating vitamin B12 levels [ref][ref]

TCN2 gene:

The TCN2 gene codes for a B12 binding protein.

Check your genetic data for rs9606756 (23andMe v4, v5):

  • AA: normal
  • AG: possibly reduced B12
  • GG: reduced B12 levels [ref][ref]

FUT2 gene:

This gene codes for an enzyme that affects glycoproteins on the cell membranes. Carriers of the AA genotype (below) do not secrete their blood type in their mucus, saliva, or semen. This changes the gut microbiome (due to intestinal mucosa changes) and also alters B12 levels. Initial studies just associated the genotype with higher B12 levels.  More recent studies point to the idea that carriers of the AA genotype may show higher B12 on a serum test, but that probably does not reflect the active B12 in the body.[ref]

In other words, non-secretors should not rely on a serum B12 test. Testing methylmalonic acid would give a better reflection of B12 status.

Check your genetic data for rs601338 (23andMe v4, v5)

  • GG: normal
  • AG: normal or slightly elevated serum B12
  • AA: can show elevated serum B12,[ref] but may not reflect true B12 status[ref]


Vegan and Vegetarian diets:
Vitamin B12 is only found in animal-based foods, so vegans and vegetarians are often deficient or marginal in their B12 status.[ref]  B12 is often added to breakfast cereals and other refined products, so eating a vegetarian diet that includes packaged and refined foods may actually result in higher B12 levels (although probably not in better health…).

It takes several years to completely deplete your liver’s store of B12, so people who have recently started a vegan or vegetarian diet may still have moderate vitamin B12 levels.[ref]

Dietary sources:
Foods that are highest in B12 include: [ref]

  • beef liver
  • mussels
  • lamb
  • caviar
  • chicken livers

High Homocysteine:
If your homocysteine levels are high and you carry the MTHFR or MTRR variants above, supplementing with vitamin B12, methylfolate, riboflavin, and B6 may help to lower your levels. [ref][ref][ref]

Supplemental B12:
Clinicians often caution people who carry the COMT rs4680 A/A genotype (lower COMT levels) to avoid methylcobalamin and stick to adenosylcobalamin or hydroxocobalamin instead. This avoids an influx of too many methyl donors for those with lower COMT enzyme levels. (Read more about COMT)

Vitamin B12 is a water-soluble vitamin with little risk of toxicity or overdose. There is no upper limit of dosage set by the US Food and Nutrition Board.

If you are older or have problems with intestinal absorption, sublingual B12 lozenges are available. Or if you are low in B12, your doctor can prescribe B12 as an injection.

In most US states, you can order your own blood tests online if you don’t want to go through your doctor and insurance. I’ve set up a way that users can access inexpensive lab tests through Ulta Lab Tests.  They are usually the cheapest option but do check around since all of these online lab companies run sales all the time.

More to read:

How Well Do You Convert Beta-Carotene to Vitamin A?

Should you take folic acid?


CBD Oil and Your Genes: Will it work for you?

CBD oil is the hottest new health hack for everything from anxiety to pain to cancer — according to the marketing geniuses.  While my skeptical side tends to go ‘pshaw…‘ when I see most of the CBD ads, there is actually some really interesting research that has come out recently.

Why do some people get such great benefits from CBD while others notice nothing? It is likely that your genes play a role in how your body responds to CBD.

This article covers the research studies on CBD, the receptors that CBD binds to, and how your genetic variants could be influencing your response (or lack thereof) to CBD oil.

Background on Cannabidiol

Cannabidiol, abbreviated CBD, is a phytocannabinoid that is part of cannabis (marijuana) and hemp plants. It was first isolated from the plant in the 1940s, and scientist unraveled its structure in the 1960s.  It is a colorless solid at room temperature and is insoluble in water.

CBD does not cause psychoactivity (feeling high). Instead, it is being used for various anti-inflammatory and antiepileptic properties.[ref]

It is legal to buy cannabidiol oil in most states in the U.S. now. But state laws vary depending on whether the CBD is derived from hemp or cannabis.

Cannabis research initially focused on THC, the psychoactive part of the plant, and the CBD component was pretty much ignored for many years. Research on CBD has exploded in the past decade with several thousand studies referencing it now.

Fun fact: Cannabis has been used for thousands of years. Researchers have been able to analyze cannabis found in a 2700-year-old grave of a shaman in China.[ref]

Your Endocannabinoid System

The psychoactive component of cannabis, Δ9-THC, binds to cannabinoid receptors in the body. These receptors are part of our endocannabinoid system. Cannabinoid receptors aren’t there just to bind to cannabis, of course. The endocannabinoid system regulates endocrine, immune, and brain functions. For example, it is involved in appetite control (which is why cannabis gives some people the ‘munchies’).[ref]

Our body produces an endocannabinoid called anandamide, which is a lipid-based neurotransmitter. Anandamide binds to the cannabinoid receptors in the central and peripheral nervous system. It plays a role in regulating mood, appetite, memory, sleep, temperature, and the development of an embryo.

But… CBD doesn’t activate the cannabinoid receptors. Instead, it acts on several other receptors, as well as modulating the response of the cannabinoid receptors.

Studies on Cannabidiol:

Looking beyond the advertising hype, here is what research studies on CBD show:

CBD is anti-inflammatory in the colon. A study used sections of inflamed colons from IBD, appendicitis, and bowel cancer patients to test the effects of CBD. The study found that CBD acts as an anti-inflammatory and prevented an increase in cytokine production in inflamed colon cells. It did not affect cancer cells in this study.[ref]

CBD has been shown in animal studies to reduce pain. This may go along with the anti-inflammatory properties or may be acting through a different mechanism. [ref] CBD has also been shown to affect pain and inflammation when applied topically. [ref]

Animal studies indicated that CBD may be able to change behavior in heroin addiction. More research is needed on this, but CBD may be something to add to addiction rehab programs. [ref]

Intestinal Barrier: 
Studies show that CBD can improve intestinal barrier function (reduce leaky gut!) for people with c. difficile infection. [ref]

Anxiety and Depression:
Several animal studies show that CBD may be effective in relieving some symptoms of anxiety.  A case study of a child with PTSD and sleep problems found that CBD was safe and effective for reducing anxiety. (More research needs to be done to know the full effects in kids!) [ref][ref] [ref]

Several animal and human studies have shown that CBD has an antidepressant effect for some people. [ref][ref]

Some specific types of epilepsy can be treated using CBD.[ref] [ref][ref]

Research shows that CBD oil induces apoptosis (cell death) in cervical cancer cells.[ref]

A cell culture study shows that CBD oil may be an effective treatment of acne vulgaris. [ref]

Caution and Safety: A cell study published in 2019 shows that CBD could cause DNA damage. DNA damage is not good.  The study needs to be replicated, of course, but it does raise some questions on CBD being entirely safe.[ref]

While most animal and human studies show CBD oil to be safe and well tolerated, even at high doses of up to 1,500mg/day, there have been side effects such as interactions with medications. It is easy to think – ‘oh, this is just something natural from a plant’ – but instead consider it a medication in regards to interactions.  [ref][ref]

CBD receptors:

Cannabidiol interacts with a variety of different receptors in the body — which explains the great variety of different conditions that it treats! These different receptors may also explain the differences in effect that people see when using CBD oil.

A little background on receptors:
Receptors are made up of a protein complex. The molecule that binds to the receptor and activates it is known as the ligand. The metaphor commonly used to describe receptors and ligands is a lock and a key.

The ligand binds to a binding site on the receptor and activates it – like a key fitting into a lock.

A  molecule that fits into the receptor but doesn’t activate it – blocks the keyhole – is referred to as an antagonist of the receptor.

A molecule that fits in the keyhole and activates the receptor (but isn’t the normal ligand) is an agonist.

This lock and key concept can get a little more complex when a molecule can bind to part of a receptor and cause the natural ligand to be either more active or less active — this is called an allosteric modulator.  A positive allosteric modulator causes the receptor to be more active.

Serotonin receptor:

Cannabidiol interacts with the serotonin receptor, 5-HT1A. This may be why, for some people, CBD oil reduces depression. There is some question as to whether CBD binds directory to the serotonin receptor or whether it is acting as an allosteric modulator, enhancing the signal of endogenous serotonin. Most of the recent studies point to it being an allosteric modulator, binding to the receptor and modifying the uptake of serotonin.ref]

Animal studies show that the effect on the serotonin receptor is not due to any effect from the cannabinoid receptor (CB1). One study showed that repeated CBD dosing for seven days “reduced nerve injury-induced anxiety-like behavior”. In other words, surgery was performed on the animals to produce nerve pain, and seven days of CBD decreased the nerve pain and decreased the anxiety from the pain. The anti-anxiety effects were shown to be due to the interaction with the serotonin receptor. [ref][ref][ref][ref]

While people commonly think of serotonin receptors in the context of neurotransmitters and depression, the body also has serotonin receptors in the gut. For people with cancer, chemotherapy often causes nausea. This is triggered by serotonin released in the small intestines. Cannabis (with THC and CBD) is often used by cancer patients to counteract nausea.

An animal study showed that CBD suppresses vomiting. [ref]

Vanilloid receptor (TRPV1):

CBD also activates and desensitized the vanilloid 1 receptor (TRPV1).

The vanilloid 1 receptor is involved in the regulation of body temperature and in sensing heat and pain. Temperatures over 109 degrees F also activate the receptor. Capsaicin, the hot spice in chili peppers, and isothiocyanate, which cause the hotness from wasabi and mustard also activate the TRPV1 receptor.

Desensitization of the receptor, such as through repeated exposure to capsaicin, decreases its activity (and pain such as from neuropathy).[ref]

CBD only acts on the vanilloid receptor at certain dosages, and the dose-effect is thought to be a U shaped curve. High doses of CBD show no effects on the TRPV1 receptors.[ref][ref]


The G-protein coupled receptor 55  (GPR55) is a receptor that is found in the central nervous system as well as the intestines, bone marrow, endothelial cells, and platelets.  It is similar to the cannabinoid receptors (CB1 and CB2) but differs structurally in a couple of ways.  CBD is a GPR55 antagonist — it blocks the function of the receptor. GPR55 is involved in axon growth and the wiring of the brain.  [ref]

It is thought that CBD’s benefit in treating epilepsy is due to blocking GPR55 and decreasing the excitation of certain neurons. A lot of research is still going on about this topic, but it is exciting to see how a natural substance can be used for children with epilepsy.[ref]

Adenosine 2A Receptor:

The adenosine 2A receptor is one of several different adenosine receptors in the body.  Adenosine is a molecule found in the body that does a bunch of different things, including being a part of ATP (adenosine triphosphate) and cellular energy.

Adenosine also acts in cellular signaling and is a neuromodulator involved in promoting sleep.  Caffeine binds to the adenosine 2A receptor, causing people to feel more awake. Additionally, the adenosine 2A receptor is involved in the immune system and in the immunomodulation of cancer. [ref]

CBD has been shown in several recent studies to bind to the adenosine 2A receptor. In cannabis use, CBD blunts cognitive impairment that Δ9-THC causes — through its effects on the adenosine 2A receptor.[ref]

An animal study of lung inflammation found that CBD decreased the effects of the pro-inflammatory cytokines (TNF and IL-6) as well as other inflammatory pathways. This study clearly showed that the anti-inflammatory effects of CBD were due to the adenosine 2A receptor. [ref][ref]

A study showed that injecting CBD into the hypothalamus increases the levels of adenosine in the brain.[ref] This may affect sleep…  One trigger for feeling the need to sleep is the accumulation of adenosine in the brain. And increased adenosine has been shown to increase non-REM sleep while decreasing REM sleep.[ref]

A rat study of CBD oil at two different concentrations showed that the total amount of sleep increased, while higher doses delayed the onset of REM sleep. [ref]

CBD has also been shown to protect against heart arrhythmia (ventricular). This was shown to be through the activation of the adenosine A1 receptor.[ref]

GABA receptors:

There is some evidence that CBD acts on the GABA receptors also. GABA is the inhibitory neurotransmitter that blocks neurons from firing. It keeps the neurons from being overexcited.

A study using magnetic resonance spectroscopy to measure both glutamate and GABA levels in the brain showed some interesting results.  The study compared 17 neurotypical men and 17 autistic men both at baseline and after a single dose of 600mg of CBD oil. The CBD increased subcortical glutamate but decreased cortical glutamate in both groups. But the results for GABA showed significant differences between neurotypical and autistic men. The GABA levels in neurotypical men increased after CBD, but the opposite happened for autistic men with a (statistically) significant decrease.  [ref]

Arachidonic Acid Release:

Both CBD and THC stimulate the release of arachidonic acid in platelets. CBD is a more potent activator of arachidonic acid than THC.  Arachidonic acid is a polyunsaturated fatty acid that can be part of the cell membrane. It is also used in the synthesis of anandamide, the endocannabinoid our body produces that binds to the cannabinoid receptor.[ref] It is possible that the release of arachidonic acid increases anandamide, thus creating some of the pleasant effects associated with CBD.

Genetic variants affecting the receptors for CBD:

The genetic variants listed below are all well-researched variants in the genes that code for receptors for CBD. BUT – there aren’t any studies (that I can find) that directly investigate the effects of CBD oil on genetic variants.  So the actual effects of these variants on CBD response is untested.

Below each variant, I’ve included what I’m going to preface as WAG (standing for ‘wild ass guess’ or ‘wisdom about genetics’ – you decide). Take it with a grain of salt. If you are a CBD or genetics researcher, leave me a comment below if these WAGs are incorrect.

TRPV1 gene:

The TRPV1 gene codes for the transient receptor potential vanilloid 1 receptor. This is involved in the body’s thermoregulation as well as pain perception from spicy foods. CBD has been shown to bind to the TRPV1 receptor in a dose-dependent manner.[ref]

Check your genetic data for rs8065080 (23andMe v4, v5; AncestryDNA):

  • T/T: normal receptor function
  • C/T: somewhat less receptor function, higher pain tolerance to cold, heat[ref]
  • C/C: less TRPV1 receptor activation[ref] higher pain tolerance to cold, heat[ref]  worse asthma symptoms[ref] less sensitive to tasting salt[ref] decreased risk of diabetes[ref]

Check your genetic data for rs161364 (23andMe v4 only):

  • T/T: decreased risk of diabetes[ref] less TRPV1(should be better able to tolerate spicy foods)
  • C/T: somewhat decreased risk of diabetes
  • C/C: normal variant

Check your genetic data for rs224534 (23andMe v4, v5; AncestryDNA):

  • A/A: less sensitive to capsaicin (skin sensitivity test) [ref]
  • A/G: normal sensitivity to capsaicin
  • G/G: normal sensitivity to capsaicin

WAG: People with two copies of the ‘risk’ allele that leads to less TRPV1 might not notice as much of an effect of CBD oil on pain.

HTR1A gene:

Cannabidiol has been shown in several recent studies to interact with the serotonin receptor, which is coded for by the HTR1A gene. Mouse studies have determined that CBD is an allosteric modulator of the serotonin receptor. This means that CBD binds to the receptor, blocking serotonin from binding to the receptor. This is how some SSRI’s work (escitalopram, paroxetine).[ref][ref]

Check your genetic data for rs6295 (23andMe v4, v5):

  • GG: increased HTR1A receptor activity (in depressed people) which caused reduced serotonin neurotransmission.[ref]
  • CG: normal receptor activity
  • CC: normal receptor activity*

*note that this is given in the plus orientation to match 23andMe data. Studies may refer to this SNP in the minus orientation. There are several studies that show opposite effects, possibly due to confusion on orientation and major allele here.

WAG: CBD oil might work better for the GG genotype for depression symptoms.

ADORA2A gene:

This gene codes for the adenosine 2A receptor.  CBD binds to this receptor, changing levels of adenosine in different tissues in the body. Caffeine is an antagonist of this adenosine receptor.[ref] Most recent studies show CBD as an allosteric modulator for ADORA2A, although some show CBD inhibiting adenosine uptake.

Check your genetic data for rs5751876 (23andMe v4, v5; AncestryDNA):

  • T/T: increased anxiety after caffeine[ref][ref] increased anxiety-related personality scores[ref] possibly less ADORA2A
  • C/T: usually no effect seen for a single copy of this variant
  • C/C: normal adenosine 2A receptor

WAG: CBD oil may reduce anxiety better for people with the TT genotype.

GPR55 gene:

This gene codes for what is now known to be an endocannabinoid receptor found in certain areas of the brain. CBD is an antagonist of GPR55, blocking the receptor.

Check your genetic data for rs3749073 (23andMe v5 only)

  • A/A: reduced receptor function, increased risk of anorexia [ref][ref]
  • A/C: somewhat reduced function
  • C/C: normal receptor function

WAG: If you have a history of eating disorders, I personally would be very cautious using CBD with the AA genotype.


Effective during acute stress:
One animal study showed that without stress (without HPA-axis activation), CBD oil didn’t act as an anxiolytic. But when animals were stressed, low and intermedia doses of CBD oil blocked the effects of acute stress on the HPA axis. [ref]

Dosages for depression:
Animal studies show that the activation of the serotonin receptors occurs at specific dosages. The lower doses do not seem to affect those receptors. [ref]

Dosages for anxiety:
A study of people with social anxiety disorder tested 600mg of CBD vs a placebo. The results showed that those treated with the CBD had considerably less anxiety and were more cognitively alert when faced with a public speaking challenge.  [ref] Another test for anxiety found that CBD was somewhat effective at 300mg. [ref]

A retrospective study of case files found that 25-75mg/day was used for sleep problems due to anxiety. All patients had a decrease in anxiety score by the end of the first month of CBD use.[ref]

As you can see, doses vary a huge amount in these studies.  But common sense (and financial sense) dictates that most people start with a lower dose and titrate up.  CBD is expensive!

What kind of CBD to buy? 
Honestly, I am not an expert on this and don’t want to steer anyone wrong. My only advice is to go with a reputable company with reviews from real people (not MLM shills).

Labdoor.com does independent testing of supplements and now has a CBD oil page.

CBD enhances adenosine signaling.[ref] Caffeine blocks the adenosine receptor…
Combining caffeine and CBD oil theoretically might decrease the effects of CBD binding to the adenosine receptor. Perhaps this would cause more of the CBD to bind with an alternative receptor – such as the serotonin receptor for the relief of anxiety/depression or the TRPV1 receptor for pain relief.  It may be worth giving it a try?

Transdermal application:
An animal study tested transdermal CBD gel for protection against alcohol-induced neurodegeneration. The results showed that a 5% CBD gel was effective for stopping part of the neurodegeneration due to alcohol, and it was detectable in plasma at this concentration. The CBD gel included both CBD and several solvents that are made for transdermal medications. [ref]
A dog study, though, found that plasma concentrations were higher when CBD was ingested as a CBD-infused oil rather than applied transdermally.[ref]

Intestinal Inflammation:
CBD has been shown in studies to counteract intestinal inflammation. It does this (at least in part) through acting on the enteric glial cells. Glial cells are part of the nervous system, and they provide support and protection for neurons.  The enteric (intestinal) glial cells surround the nerves that control the digestive system. The enteric glial cells also can release pro-inflammatory cytokines to amplify an immune system response in the gut.

Let me explain a bit:  Say that you eat some bad potato salad that sat out too long at a picnic…  your immune system will respond to the bacteria in the salad, but your enteric glial cells can help out with that immune response by releasing pro-inflammatory cytokines. This is good when your body needs to fight off the bad bacteria.  But too much inflammation on a long term basis is bad. Irritable bowel disease bad.

A study both in mice and using human intestinal cells show that CBD can reduce inflammation in the intestines. The CBD oil reduced the hyper-activation of the enteric glial cells. CBD also prevented the activation of mast cells — a type of cell that reacts during inflammation by releasing histamine and other inflammatory cytokines.  [ref]

More to read:

Cannabis and your genes: effects, dependency, and risks


Are you a spicy food wimp?

Some people thrive on spicy foods — eating the ghost pepper salsa or ordering the ‘nuclear’ hot wings. Are these people just tougher? stronger? superior? Or are they the genetic oddities?  Personally, I say that there is no shame in being a spicy food wimp!

Capsaicin is the component of chili peppers that makes them taste hot.  It binds to a specific receptor called the TRPV1 receptor, which gives us the perception of heat and pain from spicy foods.

Interestingly, birds don’t respond to capsaicin, so the hot pepper seeds don’t bother them, but most mammals avoid capsaicin due to the pain. This is an advantage for plants since seeds tend to pass on through birds, distributing the plants far and wide. Whereas mammals are more likely to destroy the seeds with their teeth not passing them on. [ref]

So why are some people less bothered by spicy foods?  Repeated exposure to capsaicin turns down the TRPV1 receptor.

Who on earth would want to eat enough spicy food to have repeated exposure? People who have variants of the TRPV1 receptors that cause them not to feel as much pain.

TRPV1 stands for transient receptor potential vanilloid 1. This is the gene that codes for the receptor that is activated by capsaicin.  This receptor is also involved in body temperature regulation.

TRPV1 is activated by:

  • temperatures greater than 43 °C (109 °F),
  • capsaicin,
  • wasabi and mustard compounds (isothiocyanate),
  • voltage,
  • acidic conditions
  • spider, centipede, and tarantula venom [ref]
  • cannabidiol (CBD oil) at certain doses[ref]

The TRPV1 receptors are mainly found in the peripheral nervous system in the nociceptive (pain-sensing) neurons. [ref]

Capsaicin cause you to feel heat and pain through activating the pain receptors in the peripheral nervous system. But repeated exposure to capsaicin will decrease the TRPV1 receptor activity, causing you to be less sensitive to pain. This is why capsaicin can be used to decreasing the pain of arthritis.

Beyond just signaling pain, the TRPV1 receptor plays other important roles within the body. It is important in the cardiovascular system and in insulin release. [ref][ref] TRPV1 activation increases insulin sensitivity and is therefore involved in energy expenditure and diabetes.[ref]

TRPV1 Genetic Variants:

Genetic variants that decrease the amount of TRPV1 should give a greater tolerance to spicy foods. These variants are also linked to less sensitivity to tasting salt and a decreased risk of diabetes.

Check your genetic data for rs8065080 (23andMe v5; AncestryDNA):

  • T/T: normal receptor function
  • C/T: normal receptor function
  • C/C: higher pain tolerance to cold, heat [ref] less TRPV1 receptor activation[ref] worse asthma symptoms[ref] less sensitive to tasting salt[ref] decreased risk of diabetes [ref]

Check your genetic data for rs222741 (23andMe v4; AncestryDNA):

  • A/A: normal
  • A/G: increased risk of migraine (more sensitive to pain?)
  • G/G: increased risk of migraines [ref] (more sensitive to pain?)

Check your genetic data for rs222747 (AncestryDNA only):

  • G/G: less TRPV1 protein,
  • C/G: more TRPV1 protein
  • C/C: more TRPV1 protein, lower levels of inflammatory cytokines in multiple sclerosis[ref]

*given here in the plus orientation to match AncestryDNA orientation.

Check your genetic data for rs161364 (23andMe v4 only):

  • T/T: decreased risk of diabetes [ref] less TRPV1(should be better able to tolerate spicy foods)
  • C/T: somewhat decreased risk of diabetes
  • C/C: normal variant

Check your genetic data for rs224534 (23andMe v4, v5; AncestryDNA):

  • A/A: less sensitive to capsaicin (skin sensitivity test) [ref]
  • A/G: normal sensitivity to capsaicin
  • G/G: normal sensitivity to capsaicin


What can you do if you are a spicy foods wimp?

  • Casein, a protein in dairy, can help break the bond between capsaicin and the receptor. Yogurt has been shown to decrease the hotness of chili peppers. [ref][source] And full-fat dairy may help more than low-fat dairy.[ref]
  • Capsaicin is an alkaloid oil, so drinking water doesn’t do much for the burn.
  • Protons can sensitize TRPV1 receptors to capsaicin. Acids are proton donors. [ref] Some online resources say that acids will temporarily give a cooling sensation, only to have the burning from capsaicin return with a vengeance.
  • Heat can also activate the TRPV1 channel, causing pain at 109 F.  But capsaicin lowers the threshold for that activation. So drinking or eating something hot along with spicy chilis will potentially cause more pain.[ref]
  • Sweets may decrease the pain intensity of eating foods with capsaicin. [ref] Combining this with dairy and cold makes ice cream a good bet for decreasing the burn from hot chilis.[ref]
  • The tip of the tongue should have the most TRPV1 channels, so perhaps shoving the hot spices further back in your mouth will help. [ref]

In mice, capsaicin reduces obesity from a high-fat diet. It also helps with insulin sensitivity.[ref][ref][ref] The human studies aren’t all that impressive for weight loss or weight loss maintenance, but there may be minor benefits for some.[ref]

If you have ever started dripping with sweat after eating something spicy, there is a name for this — gustatory sweating – and it is caused by the thermoregulation by TRPV1. [ref]  This thermoregulation is thought to be why eating spicy foods in a hot climate ends up cooling you off (theoretically).  [ref]

Capsaicin creams have been shown to be effective for arthritis pain, shingles, and muscle pain. They work by repeated exposure to capsaicin causing a decrease in TRPV1. [ref]

Capsinoids are similar to capsaicin but without the hotness. Capsinoids are found in a type of chili pepper known as CH-19 Sweet. They give the metabolic benefits of capsaicin without the spice.  [ref]

Cannabidiol (CBD oil) is a part of the cannabis plant that doesn’t get you high. It binds to the TRPV1 receptor as an agonist, and this is at least part of why it is effective for pain for some people.[ref] In theory, taking CBD oil before eating spicy foods should decrease the pain. There aren’t any studies on this, though, that I could find.