Histamine Intolerance & Genetics: Check Your 23andMe Raw Data

histamine intolerance genetics

When your body has too much histamine, it can cause symptoms known as histamine intolerance. This can be due to excess production of histamine by your body or not being able to break down histamine from foods very well.  OR… both!

Genetics plays a big role in how well your body breaks down histamine! You can use your genetic data to figure out if your genes are part of the reason why you have histamine intolerance. Knowing which genetic variants you carry leads to targeted solutions that are more likely to work for you.

Histamine Intolerance:

Classified as a biogenic amine, histamine is a molecule that plays many roles in the body. It is involved in allergic reactions, acts within our immune defense system, causes vasodilation, and is a neurotransmitter.

While most of us think of histamine only when reaching for that anti-histamine during allergy season, it is a vital part of our body’s everyday functions.

What are the symptoms of histamine intolerance?

Histamine intolerance symptoms include[ref]:

  • headaches & migraines
  • anxiety, irritability, brain fog
  • acid reflux, nausea, stomach pain
  • bloating, diarrhea, constipation
  • heart arrhythmia, dizziness
  • sinus drainage, congestion
  • hives, itching, flushing,
  • sleep problems

Most people with histamine intolerance have several of the symptoms above.[ref]

The two main causes of histamine intolerance are:

  • too little of the enzymes that are needed to break down histamine- and/or-
  • too much histamine being produced (gut microbes, mast cells degranulating, allergy).

Breaking down histamine:

Histamine is broken down by the diamine oxidase (DAO) enzyme and excreted in the intestines. So histamine that enters the body from foods or is made by the bacteria in your gut is broken down with DAO.

The histamine methyltransferase (HMNT) enzyme works throughout the body to deactivate and break down histamine created by your body.

Histamine receptors

Looking at the function of the different histamine receptors illustrates the many actions of histamine within the body.

  • H1 receptors: Smooth muscle, the endothelium (cells lining the inside of blood vessels and lymph vessels), central nervous system, and mast cells all can have H1 receptors on the surface of their cells.
  • H2 receptors: When histamine activates the H2 receptors in the stomach, acid is released. H2 receptors are also found in the intestinal tract and in the walls of blood vessels. Mast cells also have H2 receptors, which, when activated, causes the release of more histamine.
  • H3 receptors: The central nervous system and the peripheral nervous system contain H3 receptors, which act as a feedback loop for histamine levels in the CNS.
  • H4 receptors: These histamine receptors are at the core of inflammatory response.  H4 receptors are found in the bone marrow, basophils (a type of white blood cell), thymus, small intestine, spleen, colon, and mast cells. [ref]

In the intestines, which is the body’s largest immune organ, three types of histamine receptors have been found: H1, H2, and H4.  Interestingly, a study showed that people with food allergies and IBS had significantly higher levels of H1 and H2 receptors in their intestines.  [ref]

What causes mast cells to release histamine?

Mast cells are the storage site for histamine in most tissue. Allergens cause mast cells to burst (degranulate) and release histamine. Large numbers of mast cells are in the skin, bronchial tree mucosa, and intestinal mucosa. Some think that histamine intolerance is a subset of MCAS (mast cell activation syndrome).

For more in-depth info on mast cells and histamine, check out Research Studies on Mast Cells and Histamine Intolerance where I dive into all the different ways histamine can affect you.


Genetics of Histamine Intolerance:

DAO (diamine oxidase) is the enzyme produced by the intestines that breaks down histamine from foods. The AOC1 gene codes for the production of the DAO enzyme. Genetic variants in AOC1 can increase or decrease the production of the enzyme.

Note that there are rare mutations that influence DAO production not included with most genetic data, so the information below may not give you the complete picture.[ref][ref]

AOC1  genetic variants (diamine oxidase):

Check your genetic data for rs10156191 (23andMe v4; AncestryDNA):

  • C/C: normal
  • C/T: reduced production of DAO, increased risk of migraines due to histamine[ref]
  • T/T: reduced production of DAO[ref][ref], increased risk of migraines due to histamine[ref]

Check your genetic data for rs2052129 (23andMe v.5 only):

  • G/G: normal
  • G/T: reduced production of DAO, increased risk of migraines due to histamine[ref]
  • T/T: reduced production of DAO [ref], increased risk of migraines due to histamine[ref]

Check your genetic data for rs1049742 (23andMe v4 only):

  • C/C: normal
  • C/T: reduced production of DAO
  • T/T: reduced production of DAO[ref]

Check your genetic data for rs1049793 (23andMe v4; AncestryDNA):

  • C/C: normal
  • C/G: reduced production of DAO
  • G/G: reduced production of DAO [ref]

HNMT genetic variants:

Histamine n-methyltransferase is an enzyme that regulates histamine through metabolizing it from histamine into N-methylhistamine, which can then be eliminated from the body.

Check your genetic data for rs1050891 (23andMe v4, v5):

  • G/G: normal
  • A/G: reduced breakdown of histamine compared to G/G
  • A/A: reduced breakdown of histamine compared to G/G [ref]

Check your genetic data for rs11558538 (23andMe results for i3000469, v4; AncestryDNA):

  • T/T: reduced breakdown of histamine
  • C/T: reduced breakdown of histamine compared to C/C
  • C/C: normal [ref]

Methylation Cycle:
The methylation cycle plays a role in breaking down monoamine neurotransmitters including histamine.  So looking at your methylation cycle genes can also help with balancing out a histamine intolerance.


Lifehacks for histamine intolerance

Below are the research-backed solutions for histamine intolerance. You may need to try several different ‘lifehacks’ to see which works best for you.

Low histamine diet

A low histamine diet restricts the foods that contain high levels of histamine or that cause the body to release histamine.

Complete list of foods that are high in histamine 

Research studies show that a low histamine diet helps chronic urticaria (itchiness, hives), migraines, and asthma. [ref][ref]

Natural Supplements

There are DAO supplements available that may help some people who don’t produce enough of the enzyme. A recent study found that histamine intolerance symptoms improved significantly when taking DAO capsules before meals.[ref]

Pea shoots – those first few inches of the pea plant that come up in the spring –  are naturally high in the DAO enzyme.[ref] You can easily grow pea shoots at home, and they are a tasty addition to a salad.

Quercetin has also been shown in studies to inhibit mast cells from degrading. Mast cells are one way that the body releases histamine.[ref]

Gluten sensitivity

A new study looked at the correlation between symptoms of histamine intolerance and gluten intolerance.  It concluded that there was a significant overlap in symptoms and that it is possible that a low histamine diet may help people with gluten sensitivity. [ref]

Food prep to reduce histamine levels

How food is prepared makes a big difference in the histamine levels.  A recent study concluded “Frying and grilling increased histamine level in foods, whereas boiling had little influence or even decreased it. The boiling method might be helpful to control the effect of histamine in histamine-sensitive or susceptible patients, compared with frying and grilling.”

Additionally, leftovers kept in the fridge (especially meats!) can build up histamine. Instead, try putting your leftovers in the freezer and thawing them when you want to eat them.

Medications that decrease DAO

In addition to foods, drug interactions can cause a decrease in the DAO enzyme production. Metformin has been shown to decrease the DAO enzyme.

Vitamin B3 (nicotinamide or niacinamide) may increase histamine levels at doses of 100 mg or higher.[ref]


Related Genes and Topics:

Notes about Histamine and Mast Cells
A compilation of notes and reference studies on the functioning of mast cells and histamine receptors.

Tyramine: The Cheese Effect and Your Genes
Tyramine is another biogenic amine, found in a lot of the same foods as histamine. An inability to break down tyramine can cause a variety of symptoms.

 

Originally published April, 2015. 

 

COMT – A gene that affects your neurotransmitter levels

Having trouble with supplements containing methyl groups? Wondering why your neurotransmitters are out of balance? It could be due to your COMT genetic variants. This important enzyme is tasked with breaking down neurotransmitters, such as dopamine.

What does the COMT gene do?

The COMT gene codes for the enzyme catechol-O-methyltransferase which breaks down (metabolizes) the neurotransmitters dopamine, epinephrine, and norepinephrine. To do this, the enzyme adds a methyl group from SAMe to the dopamine, epinephrine, or norepinephrine molecules, thus changing them into a different substance so that the body can then get rid of it.

COMT also breaks down some drugs used for asthma, Parkinson’s, and high blood pressure. Additionally, COMT is important in the phase II metabolism of estrogens.

COMT and Altered Neurotransmitters

There are several common genetic variants that alter how the enzyme functions. Researchers link COMT genetic variants to quite a variety of different diseases from mood disorders to heart disease, possibly due to the COMT variants metabolizing neurotransmitters at different rates.

The COMT enzyme is active in the prefrontal cortex.

Some of the psychiatric disorders with increased risk associated with COMT variants include schizophrenia[ref][ref], depression [ref], anxiety, and bipolar disorder.  Keep in mind, though, that the COMT variant doesn’t cause these disorders – it just adds to the susceptibility.

Outside of the brain, COMT also breaks down estrogens.[ref][ref]  This leads to differences in the amount of the COMT available in the prefrontal cortex between males and females after puberty.

Estrogens can inhibit COMT, leading to an increase in dopamine in female brains. [ref]

Is the Val158Met SNP bad?

One of the most studied COMT genetic variants is known as Val1158Met or rs4680. This variant affects the rate at which the enzyme function. Also, known as COMT rs4680, the A/A or Met/Met variant is found in almost 20% of the population. The slightly more common G/G or Val/Val variant is found in 35-40% of the population. [ref]

There is a lot written on the internet about COMT – from Facebook groups to clinicians making videos on the topic. Often the information leads you to believe that carrying one of the other of the COMT rs4860 alleles is really bad…  Instead, the research shows there are both positive and negative effects of the variant. So instead of one allele being bad and one being good, studies show these common variants just add to our uniqueness.

Instead of focusing on bad vs good, I suggest looking at the various interactions between your genotype and supplements or lifestyle factors. Use the genetic information to optimize your health – mental and physical.

 


COMT Genetic Variants:

COMT rs4680, Val158Met

One of the most studied variants of the COMT gene is rs4680, often referred to as Val158Met.  In looking at research studies, the G is “Val” and the A allele is usually noted as “Met”.

  • The G allele (Val) has higher COMT enzymatic activity, causing a more rapid breakdown of the neurotransmitters and thus lower levels of dopamine. In most populations, the G allele is the most common.[ref]
  • The A allele (Met) has lower COMT enzyme activity and thus higher levels of dopamine.  This variant of the COMT enzyme is said to have lower activity because it breaks down faster at normal body temperature.[ref]

Check your genetic data for rs4680 (23andMe v.4 and v.5; AncestryDNA):

  • G/G: higher COMT activity, lower dopamine & norepinephrine, higher pain tolerance (Val)
  • A/G: intermediate COMT activity (most common genotype)
  • A/A: 40% lower COMT activity, higher dopamine & norepinephrine, lower pain tolerance (Met), reduced stress resiliency

Here are the findings from some studies on this COMT variant:

  • People with the A/A genotype (met/met) have been shown to get more pleasure out of pleasant events. [ref]
  • A study of adults found that those with G/G genotype had lower Neuroticism scores and higher Agreeableness and Conscientiousness scores than those with A/G or A/A.[ref]
  • A study of self-administered morphine in 973 patients following surgery found that the A allele was associated with higher morphine use.  This result backs up the many other studies showing that those with rs4680 A/A often have a lower pain tolerance than those with rs4680 G/G.[ref]
  • A study of adolescent cannabis users found that those with the G/G genotype (Val) were more likely to develop schizophrenia than those with the A/A genotype. (The risk is still small.)[ref]
  • A study of approximately 800 young adults looked at the combined effects of gender and COMT polymorphisms on schizophrenia and psychosis proneness traits.  Males carrying the G allele scored higher on the negative symptoms and traits of schizophrenia and psychosis. [ref]
  • A small 2014 study looked at the differences in fat oxidation and energy expenditure with green tea based on COMT genotype.  Those with the rs4680 G/G genotype had significantly increased energy expenditure and fat oxidation with green tea, while those with the A/A genotype had no increase. [ref]

COMT rs4633

This common variant also changes the activity level of COMT.  The T allele is the less common version, with lower COMT enzyme activity; C is the more common version with higher activity.

Check your genetic data for rs4633 (23andMe v4, v5; AncestryDNA):

  • C/C: higher COMT activity, lower dopamine, norepinephrine
  • C/T:  medium COMT activity
  • T/T: lower COMT activity, higher dopamine, norepinephrine

Recent studies on this variant have found:

  • Rs4633 T/T is associated with less back pain with lower back disc degeneration [ref] [ref]
  • A study of mercury exposure in children found that boys with the T/T genotype had impaired test performance in response to increasing acute mercury exposure.  This was in contrast to girls with the variant who showed fewer effects from acute mercury exposure. [ref]
  • A study of atherosclerosis in an elderly Japanese population found that the C/C genotype was associated with atherosclerosis, especially in women.  [ref]
  • A study found that those with T/T had a higher risk of endometrial cancer.  [ref]

Other COMT Polymorphisms:

A couple of COMT variants add to the effect of the main variants listed above.

Check your genetic data for rs6267 (23andMe v.4 and v.5; AncestryDNA):

  • G/G: typical
  • G/T: risk of higher pain sensitivity [ref][ref]
  • T/T: risk of higher pain sensitivity[ref][ref]

Check your genetic data for rs165599 (23andMe v.4 and v.5):

  • A/A: increased risk of anxiety, schizophrenia, especially in females and  in combination with rs4680 A/A[ref] [ref][ref]
  • A/G: increased risk of anxiety, schizophrenia[ref] [ref][ref]
  • G/G: typical

Lifehacks:

Methyl-donor supplements:

Clinicians often suggest that those with the rs4680 A/A genotype (lower COMT levels) avoid going overboard with foods and supplements that are considered methyl donors. Methyl donors include methylcobalamin (methyl-B12), curcumin, TMG, SAMe, theanine, and choline. [ref]  The logic behind this suggestion is that overwhelming the pathway with too many methyl groups can lead to a sudden rise and subsequent fall in dopamine levels — causing mood swings, anger, or anxiety.

Which type of B12 for low COMT?

Instead of supplementing with methyl-B12, people with rs4680 A/A genotype may want to try hydroxocobalamin or adenosylcobalamin. These types of B12 don’t contain a methyl group and are thus less likely to cause problems for people sensitive to methyl donor supplements.

Diet and Supplements

Stacking supplement: The COMT enzyme breaks down supplements that have a catechol structure. This includes quercetin, EGCG, and luteolin [ref][ref]. If you have lower COMT enzyme activity, you may want to be careful of stacking too many supplements together at the same time that are metabolized using the COMT enzyme.

A study in mice found that COMT deficiency led to glucose intolerance on a high-fat diet.[ref] Keeping in mind that this is just a mouse study, if you have blood sugar regulation issues and have COMT rs4680 A/A, you may want to look at the amount of fat in your diet. Test your blood glucose levels and keep track of whether dietary fat impacts your levels.

Magnesium is a cofactor for the COMT enzyme. A study found positive effects for liver COMT levels along with better heart health from supplementing with magnesium. A good quality magnesium supplement may be worth trying if you aren’t getting enough magnesium from food sources.

 


Related Genes and Topics:

Bipolar Disorder, Depression, Circadian Clock Genes
New research shows that depression and bipolar disorder are linked to changes or disruption in circadian genes. Some people carry genetic variants in the circadian genes that make them more susceptible to circadian disruption.

Tryptophan
Tryptophan is an amino acid that the body uses to make serotonin and melatonin. Genetic variants can impact the amount of tryptophan that is used for serotonin. This can influence mood, sleep, neurotransmitters, and immune response.

Originally published 7/2015. Updated 1/2020.

 

LDL Cholesterol

Heart disease is the leading cause of death in the US and around the world, and high LDL-cholesterol levels have been linked in many studies to increased heart disease. Standard medical advice on ideal cholesterol levels and cardiovascular disease is often confusing, ever-changing, and sometimes downright contradictory.

This article digs into the ways your genes can be involved in either high or low cholesterol levels. It includes evidence from research studies on the effects of high and low cholesterol, as well as the way that your diet and lifestyle interact with your genes and cholesterol.

Cholesterol

When you read about cholesterol and heart disease, it is easy to get the idea that cholesterol is something terrible that you don’t want in your body. But that is far from the whole picture! Cholesterol is essential for your health and wellbeing.

Cell membrane showing cholesterol molecules within the phospholipid bilayer. Wikimedia Commons.

Cholesterol is a type of lipid (fat) that is created by all animals and is an essential part of every cell as well as being important for the way your body digests foods and creates hormones.

Every cell in your body is surrounded by a membrane composed mainly of phospholipids. Cholesterol molecules make up part of that cell membrane, stabilizing the membrane to help maintain the integrity of it. Cholesterol keeps the membrane just firm enough to keep some very small water-soluble molecules out, but yet not too rigid.

In addition to being part of the structure of cells, cholesterol is also the precursor for bile acids, vitamin D, and steroid hormones.  Bile acids are essential for digesting fats in the diet, and vitamin D plays a big role in calcium metabolism and in bone health. The steroid hormones include testosterone, estrogen, progesterone, cortisol, and aldosterone.

Like most things in the body, optimal health is a matter of having neither too much nor too little cholesterol. The right amount is personal to each of us, depending on our genes, diet, age, and lifestyle.

Here is an interesting chart plotting causes of death worldwide along with cholesterol levels. The chart shows a sharp increase in mortality with low cholesterol levels and with really high cholesterol levels. One reason for the high mortality rates with low cholesterol is that cholesterol plays a role in protecting against infectious diseases.[refTrusted Source: Peer Reviewed Paper]

Don’t like charts? There is a large 10-year study out of Norway that found the lowest mortality rates occurred in people with cholesterol levels between ~190 to 270 mg/dl (5 and 7 mmol/l).[ref]

Where does cholesterol come from?

There are two sources of cholesterol: foods and endogenous production.  In addition to the cholesterol that your body makes, cholesterol from food (animal products) is absorbed in the intestines. Eating foods that contain cholesterol causes a  temporary increase in serum cholesterol levels, with levels drop to baseline in about seven hours.[refTrusted Source: Peer Reviewed Paper]

Generally, eating cholesterol causes the body to produce less of it, and decreasing your cholesterol intake will trigger the body to make more of it.  At least that is the way that it is supposed to work.

The majority of cholesterol in the body is synthesized in the liver, intestines, adrenals, and reproductive organs. It is a multi-step, complex process to make it. Cholesterol synthesis is regulated through several processes, with one of the main regulators being the SREBP protein, coded for by the SREBF1 and 2 genes.  Other genes involved in your cholesterol levels include cholesterol transport and receptor genes.

Statins and Cholesterol-Lowering Medications

Statins, one type of cholesterol-lowering medicine, is one of the most prescribed medications in the US and UK. It was estimated in 2014 that about 28% of Americans over age 40 are taking a statin. With prices for the prescription drugs ranging from $10 (generic) to over $700 for a month’s supply, the economic impact of taking statins can be extensive, especially when calculated over many years of use.  [goodRx]

The Number Needed to Treat website has an extensive review of studies on statins, including the increased risk of diabetes and muscle pain. It is an interesting, well-crafted assessment of the risks and benefits which concludes that the risks from statins outweigh the benefits for most people.  Everyone is unique. Talk with your doctor about your own specific risks and benefits.

Recent Studies on Cholesterol

Studies on both high and low LDL cholesterol show a variety of different effects:

A March 2018 study found that lung cancer patients with low cholesterol were at a 61% higher risk of death.[refTrusted Source: Peer Reviewed Paper]

A study of over 100,000 people in Denmark found that having a lifeline lower LDL cholesterol level (1 mmol/L lower) reduced the risk of Alzheimers and dementia. [refTrusted Source: Peer Reviewed Paper]

A review in the Journal of the American Medical Association in 2019 found that each “additional 300 mg of dietary cholesterol consumed per day was significantly associated with higher risk of incident” of cardiovascular disease. [refTrusted Source: Peer Reviewed Paper]

A large review in Lancet recently found that reducing LDL cholesterol reduces the risk of ‘major vascular events’. [refTrusted Source: Peer Reviewed Paper]


Genetic variants that affect cholesterol levels:

CETP Gene

One well-studied gene related to cholesterol is CETP (cholesteryl ester transfer protein), which codes for a protein involved in exchanging triglycerides between LDL and HDL cholesterol.

Check your genetic data for rs708272  Taq1B (23andMe v4, v5; AncestryDNA):

  • A/A: higher HDL cholesterol levels, lower risk of heart attack[refTrusted Source: Peer Reviewed Paper][refTrusted Source: Peer Reviewed Paper]
  • A/G: slightly higher HDL cholesterol levels and lower risk of heart attack
  • G/G: typical

Check your genetic data for rs5882 I405V (23andMe v4, v5; AncestryDNA):

  • G/G: higher HDL cholesterol levels, less cognitive decline in aging [refTrusted Source: Peer Reviewed Paper][refTrusted Source: Peer Reviewed Paper][refTrusted Source: Peer Reviewed Paper]
  • A/G: higher HDL cholesterol levels, less cognitive decline in aging
  • A/A: typical

Check your genetic data for rs3764261 (23andMe v4, v5):

  • A/A: increased HDL cholesterol levels [refTrusted Source: Peer Reviewed Paper]
  • A/C: increased HDL cholesterol levels
  • C/C: typical

 

PCSK9 Gene:

The PCSK9 gene codes for an enzyme involved in cholesterol transport. (Learn more here).

Genetic variants that decrease PCSK9 cause lower LDL-c and lower risk of heart disease.

Check your genetic data for rs11591147 R46L(23andMe v4, v5; AncestryDNA):

  • G/G: typical
  • G/T: decreased LDL-cholesterol, 30% lower risk of heart disease[refTrusted Source: Peer Reviewed Paper] [refTrusted Source: Peer Reviewed Paper]
  • T/T: decreased LDL-cholesterol, > 30% lower risk of heart disease

Check your genetic data for rs28362286 (23andMe v4; AncestryDNA):

  • A/A: decreased LDL-cholesterol, lower risk of heart disease [refTrusted Source: Peer Reviewed Paper][refTrusted Source: Peer Reviewed Paper], decreased fasting glucose levels [refTrusted Source: Peer Reviewed Paper]
  • A/C: decreased LDL-cholesterol, lower risk of heart disease, decreased fasting glucose levels
  • C/C: typical

Check your genetic data for rs67608943 (23andMe v4, v5;):

  • G/G: decreased LDL and decreased risk of heart disease [refTrusted Source: Peer Reviewed Paper]
  • C/G: decreased LDL and decreased risk of heart disease
  • C/C:typical

Check your genetic data for rs72646508 (23andMe v4, v5):

  • T/T: decreased LDL and decreased risk of heart disease  [refTrusted Source: Peer Reviewed Paper]
  • C/T: decreased LDL and decreased risk of heart disease
  • C/C: typical

Genetic variants that increase PCSK9 are linked to higher LDL-c and a higher risk for heart disease.

Check your genetic data for rs505151 (23andMe v4, v5; AncestryDNA):

  • G/G: increased LDL, increased risk of coronary artery disease[refTrusted Source: Peer Reviewed Paper] [refTrusted Source: Peer Reviewed Paper] [refTrusted Source: Peer Reviewed Paper]
  • A/G: increased LDL, increased risk of coronary artery disease
  • A/A: typical

Check your genetic data for rs28942112  (23andMe i5000370, v4; AncestryDNA):

  • C/T: greatly increased LDL, considered pathogenic for familial hypercholesterolemia[refTrusted Source: Peer Reviewed Paper]
  • T/T: typical

Check your genetic data for rs28942111 (23andMe v4, v5; AncestryDNA):

  • A/T: greatly increased LDL, considered pathogenic for familial hypercholesterolemia[refTrusted Source: Peer Reviewed Paper]
  • T/T: typical


APOB – Apolipoprotein B gene:

Apolipoprotein B is one of the main carriers of LDL cholesterol throughout the body and into the cells. Genetic variants in the APOB gene can lead to high LDL levels and an increased risk of heart disease.

Check your genetic data for rs693 (23andMe v4, v5; AncestryDNA):

  • A/A: increased APOB, higher LDL, higher triglycerides, increased risk of heart disease[refTrusted Source: Peer Reviewed Paper][refTrusted Source: Peer Reviewed Paper] [refTrusted Source: Peer Reviewed Paper]
  • A/G: increased APOB, higher LDL, higher triglycerides, increased risk of heart disease
  • G/G: typical

There are also several fairly rare APOB mutations that are pathogenic for familial hypercholesterolemia, a genetic form of very high cholesterol.  Familial hypercholesterolemia can significantly raise the risk of heart disease.

Check your genetic data for rs1444467873 (23andMe v4, v5 i4000339; AncestryDNA):

  • A/A: risk of familial hypercholesterolemia [refTrusted Source: Peer Reviewed Paper]
  • A/G: carrier for familial hypercholesterolemia
  • G/G: typical

Check your genetic data for rs5742904  (23andMe v4; AncestryDNA):

  • T/T: risk of familial hypercholesterolemia, increased risk of heart attack [refTrusted Source: Peer Reviewed Paper][refTrusted Source: Peer Reviewed Paper]
  • C/T: carrier for familial hypercholesterolemia
  • C/C: typical

Check your genetic data for rs12713559 (23andMe v4, v5; AncestryDNA):

  • A/A: risk of familial hypercholesterolemia [refTrusted Source: Peer Reviewed Paper][refTrusted Source: Peer Reviewed Paper]
  • A/G: higher LDL-c
  • G/G: typical

LDLR Gene:

Some fairly rare mutations in the LDL receptor gene are pathogenic for familial hypercholesterolemia. 23andMe data only covers a few of the over 400 mutations known.

  • rs2228671 – G allele is pathogenic for familial hypercholesterolemia
  • rs28942079 – A is pathogenic for familial hypercholesterolemia

HMGCR gene:

A genetic variant in the HMGCR gene affects how well people respond to statins.

Check your genetic data for rs3846662 (23andMe v4, v5;):

  • A/A: typical
  • A/G: statins may not work as well
  • G/G: statins may not work as well [refTrusted Source: Peer Reviewed Paper]

Lifehacks:

If you have high cholesterol and are trying to avoid going on a statin, here are some diet and supplement ideas to try:

Diet:

A whole foods diet and moderate exercise are usually beneficial for keeping cholesterol levels in check. Yep – standard advice to cut out fast food and hit the gym a few times per week.[ref] [ref] While the old advice to give up eggs has been shown to be inaccurate[ref], cutting out the processed food should decrease inflammation and lower cholesterol levels a bit. A meta-analysis that combined the data from a bunch of studies found that fruit and vegetable intake of 3+ servings per day decreases triglyceride levels (a little) and marginally improves total cholesterol. (The study found no extra benefit from consuming 5 or more servings of fruits and vegetables per day.)[ref]

Supplements:

Berberine, which is an herbal supplement, has been shown in studies to reduce both LDL and triglyceride levels. Average LDL reductions ranged from 20 to 50 mg/dL. [ref] One study found that berberine upregulates the LDL receptor, which causes a decrease in serum LDL levels. For the 32 patients in the study who had high cholesterol, three months of berberine reduced LDL by 25% and also reduced triglycerides by 35%. [ref]

Niacin (vitamin B3) has been shown to raise HDL cholesterol levels and lower LDL and VLDL levels.  There is some controversy, though, as to whether this reduces the risk of heart disease. [ref] [ref]

Fish oil:  Omega 3 or fish oil supplements are often recommended for lowering cholesterol, but not all studies show that this is true. The jury seems to still be out on the topic, but adding fish to your diet may be beneficial. [ref]

What doesn’t work:

A recent study found that pomegranate juice raised triglyceride and LDL levels, but lowered blood pressure. So you may want to skip the pomegranate juice right before a cholesterol test.
Resveratrol has been studied extensively, and the consensus seems to be that it doesn’t lower cholesterol.[ref]


Related Genes and Topics:

Triglyceride Levels
High triglycerides are linked with an increased risk of cardiovascular disease. Both genetics and diet combine to elevate triglyceride levels. Learn how your genes interact with what you eat to lower your triglycerides.

Lipoprotein (a)
High Lp(a) levels are a big risk factor for sudden heart attacks. Your Lp(a) levels are mainly controlled by your genetic variants. Check to see if you carry genetic variants that increase or decrease Lp(a).

 

Originally published 2/2015

 

HLA-B27: Genetic Variants That Increase Susceptibility to Autoimmune Diseases

HLA-B27 - check your 23andMe or AncestryDNA

Our immune system does an awesome job (most of the time) of fighting off pathogenic bacteria and viruses. But to fight off these pathogens, the body needs to know that they are the bad guys. This is where the HLA system comes in.

This article covers background information on HLA-B27 and the genetic variants available in 23andMe or AncestryDNA data.

What is the HLA system?

Human leukocyte antigens (HLA) is the part of our immune system known as the major histocompatibility complex (MHC). The HLA genes code for the proteins that help our body determine what is a foreign invader that needs to be attacked and what is ‘self’.

There are many different HLA serotypes that people can have, giving us all slightly different strengths and weaknesses against microbial diseases. But along with attacking foreign invaders, a handful of HLA types also increase the susceptibility to autoimmune diseases, where the body attacks its own cells.

HLA-B27 is linked to susceptibility to inflammatory-related autoimmune diseases including:

  • ankylosing spondylitis[ref]
  • reactive arthritis
  • psoriasis
  • inflammatory bowel disease[ref]
  • acute anterior uveitis

post infectious syndrome for shigellosis, salmonella, and chlamydia is more common in HLA-B27 positive.

What is ankylosing spondylitis (AS)?

Ankylosing spondylitis is a chronic inflammatory disease that mainly affects the spine.  It causes back pain and spinal stiffness, and the vertebrae can fuse together. This often occurs in young adults.  More info can be found on the Spondylitis Association of America site.  Carriers of HLA-B27 are at a 20-fold risk for the disease.

Why is HLA-B27 linked to autoimmune diseases?

There are multiple subtypes of HLA-B27, and the specific types associated with ankylosing spondylitis include HLA-B*2701HLA-B*2702HLA-B*2704HLA-B*2705, and HLA-B*2707.

Not everyone who carries the HLA-B27 serotype will have ankylosing spondylitis, but over 95% of people with AS carry HLA-B27.  Similarly, over 80% of people with reactive arthritis are HLA-B27 positive.[ref]  Therefore, the HLA-B27 serotype is a big risk factor for these autoimmune diseases, but it doesn’t cause the autoimmune disease by itself. Instead, there are must be other factors – environmental, pathogens, gut microbiome, diet? – that are involved. [ref]

Everyone has multiple HLA serotypes that are essential for combating pathogens. So why is this HLA-B27 more likely to lead to autoimmune conditions?

At one point, researchers advanced a theory that HLA-B27 was similar to an infecting bacterial pathogen. The idea is called ‘molecular mimicry’ and the idea is that the immune system attacks ‘self’ thinking that it is a bacteria. (Some nice YouTube videos explaining ankylosing spondylosis state that this is the reason for it…)  The problem is that newer research shows that you can create AS in an animal model without the T-cells needed for attacking a pathogen, so there is uncertainty as to whether this is actually a cause of AS.  [ref][ref]

Proteins in the body, including the HLA proteins, are made up of amino acids that join together and then fold up in a particular way.  Researchers have found that HLA-B27 has a tendency to misfold.  The specific subtypes of HLA-B27 associated with autoimmune diseases are ones that are likely to be misfolded or unfolded, causing problems when they are formed in the endoplasmic reticulum (ER). The misfoleded or unfolded proteins in the ER cause stress in that organelle, possibly causing inflammation due to an unfolded protein response mechanism.[ref]

 


Genetic Variants:

Genetic variants included in 23 and Me data that code for HLA-B27 are listed below. These variants show if you are likely to carry an HLA-B27 type. There are several subtypes of HLA-B27 and not all of them cause a higher risk of inflammatory autoimmune diseases. A blood test is still needed to be 100% certain that you carry the HLA-B27 type associated with autoimmune diseases.

Check your genetic data for rs4349859  (23andMe v5 only; AncestryDNA):

  • A/A: high likelihood of carrying 2 copies of HLA-B27[ref][ref][ref]
  • A/G: high likelihood of carrying 1 copy of HLA-B27
  • G/G: normal

Check your genetic data for rs13202464 (23andMe v4, v5; AncestryDNA):

  • G/G: high likelihood of carrying 2 copies of HLA-B27[ref][ref][ref]
  • A/G: high likelihood of carrying 1 copy of HLA-B27
  • A/A: normal

 



Lifehacks:

Keep it in perspective:
Don’t freak out if you are a carrier of HLA-B27. In Caucasians, about 10% of people carry one copy, whereas only 1% of African populations carry HLA-B27.[ref]

If you want to get the blood test for HLA-B27 and you can’t get it through your doctor, you can order it on your own in the US. UltaLab Tests is one place that I use. There are other websites as well, so shop around for the best price.

Although HLA-B27 increases the risk of ankylosing spondylosis by 20-fold, it is still a rare disease with about 1 in 2000 people having it.[ref] If you have the HLA-B27 serotype, the lifetime absolute risk is about 6%.[ref]  There are other genetic variants thought to be involved in the risk for ankylosing spondylosis,  as well as environmental factors.[ref]

Survival advantage:
Interestingly, carriers of the HLA-B27 have a survival advantage for HIV and hepatitis C.[ref]

Gut Microbiome:
There is also a connection between HLA-B27 and changes to the gut microbiome.[ref] Spondylitis patients also showed changes in the gut microbiome with decreased F. prausnitzii and increased Bacteroides fragilis.[ref] You may want to get a gut microbiome test done to see if everything is in order down there.

Reactive Arthritis:
If you carry the HLA-B27 type and also have reactive arthritis, there is an interesting tie to salmonella persistence or other microbial infections.

Probiotics:
Animal studies show that Lactobacillus G/G probiotics may help with preventing recurrence of inflammatory bowel problems associated with HLA-B27.[ref]  Although I couldn’t find a human clinical trial on it, if you are wanting to try a Lactobacillus G/G probiotic, Culturelle contains that strain.

Autoimmune Paleo (AIP) diet:
The link between diet and symptoms of reactive arthritis or ankylosing spondylitis isn’t clear.  A meta-study looked at a bunch of studies on the subject and found no statistical links with diet. But individuals report that diet can make a difference in their joint pain with certain foods making it worse.  So trying an elimination diet or the autoimmune protocol diet may be worthwhile.


Related Genes and Topics:

CTLA-4 – General Autoimmune Risk Factor
The CTLA4 gene codes for a protein that is important in the immune system. It acts as a checkpoint that can downregulate your immune system response. Genetic variants in the CTLA4 gene can increase your risk for several different autoimmune diseases.

Psoriasis Genes
Psoriasis is an autoimmune condition that causes dry, sometimes itchy patches of skin. It is caused by the immune system attacking your skin cells, speeding up the turnover of the cells. Genetics plays a role in your susceptibility

 

Originally published 07/2018. Updated 1/2020.

Glucuronidation: UGT genetic variants, phase II detoxification

The UGT family of enzymes are responsible for an important part of phase II detoxification. In this article, I’ll explain what the UGT enzymes do in the body, how your genes impact this part of detoxification, and lifestyle factors that can increase or decrease this detox process.

Brief background: When foreign substances such as pollutants or prescription medications enter your body, the substances are broken down and then eliminated. This whole process is referred to as phase I and phase II detoxification. Phase I detoxification uses the CYP enzymes to oxidize the toxic substance. Then in phase II, the toxic substance is altered again to make it water-soluble. This allows your body to easily excrete the substance.

UGT Enzymes: Glucuronidation

The UDP-glucuronosyltransferase (abbreviated UGT) enzymes facilitate a glucuronidation reaction. This is just a term that means that one of the UGT enzymes helps to make a substance more water-soluble so that it can be excreted through urine or feces.

This is important because the phase I detoxification intermediates often cause oxidative stress or other problems in the body. You don’t want them hanging around, damaging cells or DNA.  Thus, this phase II process needs to act in sync with phase I, making the substance water-soluble so that it can be quickly eliminated.

Glucuronidation reactions are used by the body to inactivate and eliminate:

  • bilirubin (from the breakdown of old red blood cells)
  • retinoids (vitamin A components)
  • estrogens and testosterone [ref ]
  • BPA and BPS[ref ][ref ]
  • cortisol
  • certain fatty acids (DHA, oleic acid, linoleic acid) [ref ]
  • a lot of medications[ref ],  including acetaminophen (Tylenol)[ref ]
  • certain pesticides[ref ]
  • polycyclic aromatic hydrocarbons (PAHs – carcinogenic) [ref ]

There are many different genetic variants in the UGT family of enzymes. Thus, some people may be more sensitive to certain medications or have a harder time breaking down and eliminating substances such as BPA.


UGT Genetic Variants:

The UGT family of genes codes for the enzymes needed for glucuronidation. Variants in these genes are fairly common, and the variants can increase or decrease the body’s ability to detoxify substances through glucuronidation.

UGT1A1 Gene:

UGT1A1 is involved in the breakdown of bilirubin, estrogen, and several carcinogens. Bilirubin is a  product naturally created in the body as it clears out aged red blood cells. The UGT1A1 enzyme is responsible for the final step in making bilirubin easy for the body to get rid of. It is excreted in bile and the urine (it’s what makes your poop brown).

Gilbert’s Syndrome is associated with this gene and involves bilirubin not being broken down appropriately. This syndrome leads to periodical increases in the level of unconjugated bilirubin, especially in times of physical stress such as illness, intense exercise, or fasting.  This is a fairly common disorder with symptoms that include periodic yellowing of the eyes, abdominal pain, and fatigue.

There is a common variant known as UGT1A1*28 that is associated with higher bilirubin levels in Caucasian and African populations. There are questions/discrepancies surrounding the validity of the data on this in older 23andMe versions, and the data is not found in newer 23andMe or AncestryDNA versions. If you have data from another source, look for rs3064744.

Check your genetic data for rs4148323  (23andMe v4, v5; AncestryDNA):

  • A/A: UGT1A1*6 – increased bilirubin level, Gilbert’s syndrome (in Asian and Indian populations)[ref ][ref ], possibly decreased estrogen metabolism [ref ] may alter dosing for irinotecan (cancer drug) [ref ]
  • A/G: Carrier of UG/T1A1*6 (somewhat reduced enzyme activity)
  • G/G: normal

Check your genetic data for rs4124874 (23andMe v4, v5; AncestryDNA):

  •  G/G: UGT1A1*60[ref ], reduced enzyme activity, increased bilirubin (Caucasian populations)[ref ][ref ]
  • G/T: one copy of UGT1A1*60
  •  T/T: normal

Check your genetic data for rs6742078 (23andMe v4, v5; AncestryDNA):

  •  T/T: reduced UGT1A1 activity, increased gallstone risk (males)[ref ] increased bilirubin[ref ]
  • G/T: somewhat reduced activity
  •  G/G: normal

Check your genetic data for rs8330 (23andMe v5; AncestryDNA):

  • C/C: normal
  • C/G: intermediate UGT1A1 activity
  • G/G: slower UGT1A1 activity [ref ]

Check your genetic data for rs35003977 (23andMe v4; AncestryDNA):

  •  T/T: normal
  • G/T: higher bilirubin, Gilbert’s syndrome possible
  •  G/G: high bilirubin and possible Gilbert’s syndrome[ref ]

UGT1A6 Gene:

UGT1A6 is also involved in transforming bilirubin, hormones, and certain drugs (aspirin, acetaminophen) into water-soluble metabolites that can then be excreted from the body.  Studies on this gene also look at the variants in association with benzene poisoning.

Check your genetic data for rs17863783 (23andMev4, v5;AncestryDNA):

  •  T/T: increased UGT1A6, protective against bladder cancer[ref ]
  • G/T: increased UGT1A6
  • G/G: normal

UGT1A9 gene:

Check your genetic data for rs6714486 (23andMe v4 only)

  • A/A: higher activity [ref ] [ref ]
  • T/T: normal

 


Lifehacks:

If your genetic data shows that you have slower than normal UGT activity, you may want to look into the following:

Speeding up UGT enzymes:

Cruciferous vegetables cause your body to increase the production of UGT1A1. Cruciferous veggies include broccoli, kale, Brussels sprouts, cauliflower, and cabbage.

If you aren’t eating enough cruciferous veggies, supplements of I3C and DIM (diindolylmethane) are available. They are produced from the part of the cruciferous veggies that induce UGT1A1. [ref ]

Quercetin (flavonoid supplement) and curcumin (from turmeric) both increase UGT enzyme activity, according to an animal study.[ref ]

Avoid toxicants that utilize the UGT enzymes:

  • UGT1A1 is also responsible for the breakdown of BPA (in plastics) and BPF. Avoiding these substances may be more important if you carry a slow UGT variant.
  • The chemicals perfluorooctanoate (PFOA) and perfluoro octane sulfonate(PFOS) have recently been shown to inhibit UGT1A1.[ref ]

Gut Microbiome Connection

Certain gut bacteria produce an enzyme called β-glucuronidase.[ref ][ref ][ref]  This enzyme basically reverses the glucuronidation reactions that the UGT enzymes caused.  Thus, when the toxic substances that were glucuronidated in phase II detoxification reach the intestines, the process can be reversed by β-glucuronidase. This allows the body to reabsorb the toxic substance again via the intestines. Generally, not a good thing.

Lower levels of β-glucuronidase are linked to a lower risk of colon cancer.[ref ][ref ]

A recent study looked at the effect on β-glucuronidase from increasing the amount of fruits and vegetables in the diet. The study found that higher fruit and vegetable intake increased β-glucuronidase activity. [ref ]

Calcium d-glucarate is often promoted as a supplement for decreasing β-glucuronidase. I had a really hard time finding studies that show this, other than an animal study from 1990 using a diet with 4% calcium glucarate.[ref ]

The right probiotic strains may reduce β-glucuronidase activity. An animal study showed that fermented milk with several lactobacillus strains reduced β-glucuronidase.[ref ]


Related Genes and Topics:

How your genes influence BPA detoxification:
BPA, a chemical found in some plastics, has been linked to a variety of effects on people including obesity, insulin resistance, and epigenetic effects on the fetus. Genetics plays a role in how quickly you can eliminate BPA from your body.

Nrf2 Pathway: Increasing the body’s ability to get rid of toxins
The Nrf2 (Nuclear factor erythroid 2–related factor) signaling pathway regulates the expression of antioxidants and phase II detoxification enzymes. This is a fundamental pathway that is important in how well your body functions. Your genetic variants impact how well this pathway functions.

 

Originally published Jun 3, 2015

Alpha-1 Antitrypsin Deficiency

A genetic mutation in the SERPINA1 gene causes alpha-1 antitrypsin deficiency. This increases a person’s susceptibility to COPD (chronic obstructive pulmonary disease) and, in some cases, cirrhosis of the liver.

As far as rare mutations go, the alpha-1 antitrypsin deficiency mutations are fairly common and pop-ups on 23andMe or AncestryDNA data more often than you would think. For a lot of people, it is one of those lightbulb moments of – such as ‘this is why Mom/Dad had COPD at a relatively young age’.

What is alpha-1 antitrypsin?

Alpha-1 antitrypsin is an enzyme produced in your body.  The SERPINA1 (serine protease inhibitor 1) gene codes for the alpha-1 antitrypsin protein. Alpha-1 antitrypsin was named a while ago – before the function was fully understood –  so its name is a bit misleading.

In your lungs, there is a protein called elastin that is produced by certain cells.  Elastin increases the elasticity and strength of the lung tissue in the alveoli, which are the tiny air sacs where oxygen is exchanged with carbon dioxide.

Elastin, though, isn’t unique just to your lung cells. The elastin protein is also produced by Gram-negative bacteria, so your immune system (specifically the neutrophils), creates an enzyme called elastase to break apart the elastin in the outer membrane of the bacteria.

Elastase is great – when you need to get rid of bacteria. But you don’t want too much elastase hanging around, because it can also break down the elastin in the cells in your lungs.

Alpha-1 antitrypsin comes into play here. It is a protease inhibitor – which means that it inhibits a protein that breaks down other proteins. Specifically, alpha-1 antitrypsin inhibits elastase so that it won’t break down your lung cells.

Alpha-1 antitrypsin is made in the liver and then transported to the lungs. In the lungs, it deactivates elastase before it damages lung cells.  Pretty neat system – elastase can attack gram-negative bacteria in the lungs, but alpha-1 antitrypsin keeps it from damaging your own lung cells.

What is alpha-1 antitrypsin deficiency?

Certain mutations in the SERPINA1 gene can cause alpha-1 antitrypsin deficiency due to the alpha-1 antitrypsin protein not functioning appropriately. Alpha-1 antitrypsin deficiency is thought to be one of the most common hereditary diseases worldwide. [ref]

Alveoli in the lungs can lose their elasticity.

Without alpha-1, there can be too much elastase, causing damage to lung tissue.  The damage occurs in the alveoli. When the alveoli lose some of their elasticity, it can cause problems with easily bringing in oxygen and moving out CO2.

People who carry alpha-1 antitrypsin deficiency mutations are more likely to have COPD – chronic obstructive pulmonary disease.

COPD causes shortness of breath, wheezing, cough, and mucus production. Other terms for COPD include emphysema and chronic bronchitis.

As you can imagine, smoking is really bad for people with alpha-1 antitrypsin deficiency. Carriers of the alpha-1 antitrypsin deficiency mutations are at a much higher and earlier risk of COPD compared with smokers without the mutation.

The liver produces alpha-1 antitrypsin in response to signals from the body for illness (fever, inflammatory signals). This is so that it counteracts the neutrophil’s production of elastase at a time when the neutrophils are actively combating an infection. [ref ]

Common alpha-1 antitrypsin deficiency mutations

There are two mutations for alpha-1 antitrypsin deficiency that are more common. They are known as Pi*Z and Pi*S. The mutations cause differences in the alpha-1 antitrypsin enzyme, and there can be different outcomes based on which mutation a person carries.

If you are reading through the research on alpha-1 antitrypsin deficiency, the normal version of the gene is referenced as Pi*M.

The Pi*Z and Pi*S mutations cause the alpha-1 trypsin protein to be misfolded when it is produced in the liver.  Because the shape of the protein is altered, the mutant alpha-1 antitrypsin will get stuck within the liver, unable to make it to the lungs. The mutant proteins that are stuck in the liver cells increase the risk of cirrhosis (liver damage/failure).

SERPINA Pi*Z mutation:

About 1% of Caucasian populations carry one copy of the SERPINA1 mutation referred to as Pi*Z.

In people with two copies of the Pi*Z mutation, both the lungs and the liver can be affected. Cirrhosis is a common complication, in addition to COPD. Infants with two copies of the Pi*Z are likely to have jaundice. [ref ]

People who carry one copy of the Pi*Z mutation are more likely to have COPD if they smoke. They are also likely to have decreased lung function.[ref ]

Check your genetic data for rs28929474 (23andMe v4, v5; AncestryDNA *):

  • T/T:  two copies of Pi*Z mutation, alpha-1 antitrypsin levels often less than 30% of normal [ref ]
  • C/T: one copy of the Pi*Z mutation
  • C/C: normal

SERPINA Pi*S mutation:

The Pi*S mutation also causes decreased alpha-1 antitrypsin. Carriers of the Pi*S mutation are at a higher risk for liver fibrosis. [ref ]

Check your genetic data for rs17580 (23andMe v4, v5; AncestryDNA *):

  • T/T:  two copies of Pi*Z mutation
  • C/T: one copy of the Pi*Z mutation
  • C/C: normal

Carriers of one copy of the Pi*Z or Pi*S mutation are at a higher risk of having problems with lung function, especially in smokers.[ref ]

Carriers of one copy of the mutations are also at a higher risk of cirrhosis with heavy alcohol consumption.[ref ]

*All rs id data is given in the plus orientation to match with 23andMe and AncestryDNA genetic raw data format.

Interaction with other Genes:

Our genetic variants act together not only with environmental factors but also with other genetic changes.

The TNF gene codes for the inflammatory cytokine, TNF-alpha, which is part of the body’s immune response system. Higher amounts of TNF-alpha can cause chronically increased inflammation. Researchers studied the TNF genetic variants in a group of people who have Alpha-1 Antitrypsin Deficiency and found that carrying a specific TNF variant doubled the likelihood of the carriers having chronic bronchitis. [ref]

Check your genetic data for rs361525 (23andMe v4, v5; AncestryDNA):

  • A/A:  increased likelihood of having chronic bronchitis with Pi*Z mutation
  • A/G: increased likelihood of having chronic bronchitis with Pi*Z mutation
  • G/G: typical

Heterozygous advantage

When mutations that cause a genetic disease are more common in the population than they statistically should be, researchers often check to see if there is an advantage for people who carry one copy of the mutation.  For example, people who carry one copy of the sickle cell anemia mutation are more resistant to malaria. The sickle cell mutation is more commonly found in people who live in Africa, where malaria is highly prevalent. People who carry one copy of the sickle cell mutation are more likely to survive malaria, thus passing on the mutation to their children.

A study published in 2016 looked at several different genetic diseases to see if there was an advantage to carrying one copy of the mutation.  For alpha-1 antitrypsin deficiency, the researchers found that carriers of one copy of the Pi*Z mutation tended to be taller (1.5cm on average) and also had greater initial lung volume. This could lead to a survival advantage for babies. [ref ]

Learn more

Your doctor can run tests to see what your alpha-1 trypsin levels are. If you carry one copy of the mutation and drink or smoke, it would be a good idea to talk with your doctor.

Here are a couple of excellent resources for more information:

 

Quercetin: Scientific studies + genetic connections

Quercetin is a natural flavonoid that acts both as an antioxidant and anti-inflammatory. This potent flavonoid is found in low levels in many fruits and vegetables, including elderberry, apples, and onions.

As a supplement, quercetin has many positive health benefits. This article focuses on the results of clinical trials involving quercetin as well as linking to specific genetic topics. By using your genetic data, you can make a more informed decision on whether quercetin is worth trying.

Quercetin Research:

Quercetin has been shown in cell studies to be a fabulous, wonder-supplement for lots of different conditions. But… the studies in humans don’t always match up with the cell studies and animal studies. I’m going to focus mainly on the human trials of quercetin and go into the cell studies just a bit in reference to genetics.

Food sources of quercetin:

Quercetin is a flavonol found in low levels in a lot of different fruits and vegetables.  Here is a list of foods with a higher quercetin content (from Phenol-explorer and the USDA)

  • Capers: 234mg/100g
  • Black elderberry: 42 mg/100g
  • Dark chocolate: 25 mg/100g
  • Shallots and onions: 10 – 31mg/100g
  • Apples, with skin: 2 -4 mg/100g
  • Billberry: 1.27/100g
  • Red Wine: 0.83 mg/100 ml
  • Apple juice: 0.48 mg/ 100ml

Blood pressure reduction studies that use quercetin

In a double-blind randomized placebo-controlled study, quercetin reduced blood pressure in men with hypertension. The study used 730 mg/day of quercetin and found that it reduced systolic blood pressure by 7 mm Hg and diastolic blood pressure by 5 mg Hg. [ref Trusted Source: Peer Reviewed Journal]

Another study using a smaller dosage of quercetin had a smaller decrease in blood pressure.  The study results showed a decrease in systolic blood pressure of 3.6 mm HG in overweight patients with high blood pressure using only 162 mg/day of quercetin.[ref Trusted Source: Peer Reviewed Journal]

A meta-analysis that combined the data from 7 clinical trials found that there was a significant reduction in blood pressure in randomized controlled trials that uses dosages of more than 500mg/day. [ref Trusted Source: Peer Reviewed Journal]

Quercetin for oxidative stress and oxidized LDL

When a cell has an imbalance of reactive oxygen species (ROS) to antioxidants, it is referred to as oxidative stress. These reactive oxygen species contain an unstable balance of electrons and can cause reactions that are damaging to the cell.  Too much oxidative stress can cause DNA damage, the production of inflammatory signals, and eventually cell death.

Quercetin is a free radical scavenger that has been shown in studies to help prevent oxidized cholesterol [ref Trusted Source: Peer Reviewed Journal] This is important because oxidized cholesterol may accelerate atherosclerosis, or plaque build-up in the arteries.[ref Trusted Source: Peer Reviewed Journal]

A double-blinded, placebo-controlled cross-over trial in overweight adults with metabolic syndrome found that 150mg/day of quercetin decreased the concentration of oxidized LDL cholesterol.  There wasn’t much of an effect on any other health markers else at this dosage, but just decreasing the oxidized LDL should decrease the risk of cardiovascular disease. [ref Trusted Source: Peer Reviewed Journal]

Researchers theorize that oxidative stress contributes to Alzheimer’s disease pathology. Animal and cell studies show that quercetin can protect against oxidative stress in the brain and partially prevent the associated neuronal toxicity.[ref Trusted Source: Peer Reviewed Journal]

Most of the time, preventing oxidative stress is something that you want to do – but not always.  One of the benefits of exercise is to create stress, which causes cells to respond by adapting and producing more mitochondria. Quercetin effect on exercise performance has been researched. Results of the studies have varied, but most show that quercetin doesn’t increase exercise performance.[ref Trusted Source: Peer Reviewed Journal] If you are supplementing with quercetin, consider whether you should take it at a time that it won’t interfere with the benefits from exercise induced stress.

Related article: Athletic Performance Genes

Quercetin as a senolytic (longevity benefits)

Cellular senescence occurs when a cell can no longer divide or do its normal function. Basically, the cell just sits there giving off proinflammatory signals. Those inflammatory factors can then impact the surrounding cells.  Kind of like a meth dealer moving into the neighborhood…  not good for the neighbors.

The body can get rid of senescent cells pretty well  — up to a point.  But when too many senescent cells accumulate, things start going downhill.  Recent research points to senescent cells actually causing a lot of the diseases of aging, rather than just being a symptom of aging.

Clearing out senescent cells could either delay or possibly reverse aging. That would be pretty cool…

Quercetin has been studied recently as a senolytic –  a way of clearing out senescent cells. Animal and cell studies are promising.[ref Trusted Source: Peer Reviewed Journal][ref Trusted Source: Peer Reviewed Journal]

But what about human trials?  When quercetin is combined with Dasatinib (a leukemia drug), it clearly reduces senescent cells. [ref Trusted Source: Peer Reviewed Journal][ref Trusted Source: Peer Reviewed Journal] This is an exciting field of study that shows a lot of promise for the future.

One more way that quercetin may improve atherosclerosis and oxidized LDL is by reducing senescent cells in the endothelium (lining of the arteries).  A new study out looked at quercetin’s effect on a cell model of atherosclerosis. The study found that quercetin inhibited the foam cells created by oxidized LDL in atherosclerosis and it also decreased senescent cells. While just a cell study, this points to quercetin possibly having multiple beneficial effects in cardiovascular disease. [ref Trusted Source: Peer Reviewed Journal]

Related article: NAD+

Advanced glycation end products:

The production of advanced glycation end products (AGEs) in the body (and through foods we eat) increases the diseases of aging.  For AGEs that are produced in the body, methylglyoxal levels are important.

A randomized, double-blind, placebo-controlled crossover trial found that 160 mg/d of quercetin reduced methylglyoxal, a precursor for AGEs by an average of 11% after 4 weeks. [ref Trusted Source: Peer Reviewed Journal]

Related article: Advanced Glycation End Products

Uric acid:

High uric acid levels are a risk factor for gout.  A double-blind, placebo-controlled cross-over trial in healthy men with higher uric acid found that quercetin lowered uric acid levels.  The trial used 500mg/day of quercetin for four weeks and decreased uric acid by 26·5 µmol/l  on average.[ref Trusted Source: Peer Reviewed Journal]

Rheumatoid Arthritis:

Since quercetin can reduce both pain and inflammation, it makes sense that it could help with rheumatoid arthritis.  Indeed, a two-month placebo-controlled trial found that quercetin reduced morning pain, stiffness, and post-activity pain. Quercetin also reduced TNF-alpha (inflammatory cytokine) levels.   The trial included 50 women with RA who took either 500mg/day of quercetin or a placebo.[ref Trusted Source: Peer Reviewed Journal]

Related article:TNF-alpha and rheumatoid arthritis

Immune boosting

A randomized placebo-controlled trial found that 12 weeks of quercetin at 1000mg/day reduced upper respiratory tract infections.[ref Trusted Source: Peer Reviewed Journal]

Excessive exercise can make you more susceptible to getting sick.  In a mouse trial where the mice exercised to fatigue (treadmill) for days, researchers found that quercetin offset the increased propensity to get sick after exercising to fatigue.[ref Trusted Source: Peer Reviewed Journal]  This may be something to try if you are training for an upcoming exercise-intensive event.

A human study showed that quercetin was safe (>5g/day) and effective for some people in reducing the viral load in hepatitis C patients.[ref Trusted Source: Peer Reviewed Journal]

Mast Cell Blocker

Mast cells are an important part of the immune system that can degranulate and signal for an inflammatory response. Overactive mast cells can be a problem, leading to allergic responses or to mast cell activation syndrome. One compound that mast cells can release is histamine.

Quercetin has been shown to stabilize mast cells and inhibit the release of histamine.[ref Trusted Source: Peer Reviewed Journal]

Related article: Histamine and Mast Cells

Caffeine and quercetin (CYP1A2 gene):

Quercetin inhibits CYP1A2, which is the enzyme the body uses to metabolize caffeine.[ref] If you are a slow metabolizer of caffeine, quercetin along with caffeine may mean that you feel the effects of caffeine for a longer period of time.

Relevant articles: CYP1A2 Variants

Absorption, transport, and metabolism

For any substance to have an effect in the body, it needs to be absorbed (usually in the intestines), transported throughout the body, and the broken down and eliminated (usually through the liver.  One big difference between cell studies and in vitro human studies is the absorption and metabolism of substances.

Absorption of quercetin:

A study found that the bioavailability of quercetin in humans is about 45%. The half-life is quercetin is between 11-28 hours, so taking it daily will build up more than just what was consumed that day.[ref Trusted Source: Peer Reviewed Journal]

Researchers have looked at the interaction between different types of foods and the absorption of querceting. They found that eating a meal that contains fat along with the quercetin supplement can increase bioavailability.[ref Trusted Source: Peer Reviewed Journal]  Alternatively, if you normally take a fish oil supplement, you may want to take it at the same time as your quercetin.

Transdermal absorption of quercetin is an interesting idea, especially with the antioxidant properties and the possibility of enhancing the skin. Since it is hydrophobic, quercetin won’t dissolve well in water.  One study found that olive oil and soybean oils were better for transdermal absorption, compared to avocado, raspberry seed, and coconut oils.[ref Trusted Source: Peer Reviewed Journal] Another study used solid lipid nanoparticles with quercetin to enhance skin absorption.[ref Trusted Source: Peer Reviewed Journal]  (Personal note…   quercetin is a yellow-ish powder that stains everything it touches. When mixed with olive oil, it lends a jaundiced-hue to skin.)

Metabolism  and interactions:

Quercetin is an inhibitor of the CYP2C8 enzyme. If you have genetic variants that slow down the CYP2C8 variant and stack quercetin with a medication that uses that enzyme, you could majorly impair the metabolism of the medication.

Related article: CYP2C8 Genetic Variants

Quercetin has a catechol structure and is partly metabolized through the COMT enzyme.  If you carry the slower version of COMT, you may want to be careful and not go overboard with quercetin.

Related article: COMT variants

Transport of quercetin:

The MATE1 (multidrug and toxic compound extrusion transporter-1) protein is the quercetin transporter. It is coded for by the SLC47A1 gene. [ref Trusted Source: Peer Reviewed Journal]

What quercetin doesn’t do…

I don’t want to leave you with the impression that quercetin is a miracle cure for everything. Far from it! Instead, it may be another tool to use for a specific purpose at the right dosage.

For example, a trial of 162 mg/d of quercetin for six weeks showed little effect on C-reactive protein, leptin levels, or blood glucose levels in overweight adults with metabolic syndrome. The study did show that the 162 mg dose was safe. [ref Trusted Source: Peer Reviewed Journal]

Another study in healthy adult women found no significant effect from either 500 mg/day or 1000 mg/day on inflammatory markers and immune function. [ref Trusted Source: Peer Reviewed Journal]

The studies that show more of an effect seem to be using higher dosages (500-1,000 mg/day). Plus, it may be more effective in people who have a problem (e.g. high blood pressure or cholesterol) rather than having a large effect for people who are healthy.

Where to get quercetin:

You can get quercetin as a supplement at your local health food store or on Amazon in capsules or as a powder*.  The advantage of getting it as a powder and either putting it in a smoothie or into capsules yourself is that you can eliminate the excipients in most capsule formulas. The drawback to the powdered form is that it is yellow and will stain everything that it touches a bright yellow. The stains do eventually come out of kitchen towels…  lessons learned.

*Affiliate link: Links to Amazon are not a recommendation for a certain brand or product. Please read the reviews and decide for yourself.

Plant Sterols for Lowering Cholesterol Depends on Genetics

One recommendation often made for lowering cholesterol levels is to consume higher amounts of plant sterols.  You can find plant sterols in supplements such as beta-sitosterol or spreads like Benecol or SmartBalance margarine. These butter alternatives are marketed as a heart-healthy way to help you lower cholesterol and prevent cardiovascular disease (CVD).

It turns out that plant sterols probably lower cholesterol only in people with certain genetic variants. Plus, in an interesting twist, people with genetic variants that cause greatly increased plant sterol levels are actually at a higher risk of atherosclerosis and CVD.

So the question is – are plant sterols good or bad for you? The answer depends, in part, on your genes. Let’s dig into the science here so that you can make better choices than just relying on marketing garbage for your health decisions.

Cholesterol and Plant Sterols

Heart disease is the number one killer of people worldwide, and high cholesterol levels are a risk factor for heart disease. There are differing opinions about high cholesterol risks and the role of cholesterol in heart disease. Since research tends to support the link between high cholesterol levels and heart disease, stick with me here, and we can discuss the complexity later.

In general, high triglycerides and high LDL cholesterol levels are something that most doctors will worry about. Recommendations for dietary interventions often include limiting saturated fat and adding in plant sterols. [ref Trusted Source: Peer Reviewed Journal] Your genetic variants may play a bigger role in whether plant sterols will work for you (and also how much of an impact saturated fat has, but that is another article).

Background on cholesterol:

Cholesterol is a general term for a type of lipid known as a sterol that is present in animal cells. There are several types of cholesterol made in the body, and you can also consume cholesterol in foods.

Cholesterol is transported in the blood attached to a lipoprotein – such as very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL),  high-density lipoprotein (HDL) and chylomicrons.  LDL particles are the most common cholesterol carriers.

What does cholesterol do?

Cholesterol is used by all the cells in the body as part of the cell membrane. Within the cell membrane, cholesterol can stabilize the membrane, causing less fluidity in the phospholipid bilayer.

Detail of cell membrane. Cholesterol shown in yellow. (Public domain image)

Cholesterol is also a precursor molecule for vitamin D, bile acids, and steroid hormones. While often demonized as something ‘bad’, cholesterol is essential for your body to function.

Regulation of cholesterol:

In general, the body tightly regulates the level of cholesterol that is present at any given time. If you eat more cholesterol, your liver should make less of it. If you don’t eat many foods containing cholesterol, your body will increase cholesterol production.

Bile acids are created using cholesterol that is oxidized by the liver and then bound to glycine, taurine, or sulfate molecules. Your body uses bile acids to break down and digest fats from foods, and then the bile acids are mostly reabsorbed in the intestines and recycled. Some cholesterol, though, is lost each day via excretion of bile acids through the colon.

Cholesterol from food:

Almost all of the cholesterol that you get via your diet is from animal-based foods. The cholesterol that you eat gets absorbed into the cells lining the small intestines, and people vary in how much cholesterol they absorb. There are a couple of different transporters involved in moving cholesterol from the intestinal cells. Plus, not all cholesterol from food ends up being absorbed and used by the body.  [ref Trusted Source: Peer Reviewed Journal]

Plant sterols:

Most plants produce very, very little cholesterol.[ref Trusted Source: Peer Reviewed Journal] Instead, they contain a type of sterol known as phytosterols, which is a term that covers both plant sterols and plant stanols. Plant sterols, such as sitosterol, function similarly to cholesterol in the way that they regulate the fluidity of the cell membrane.

In general, people can absorb about 5% of dietary plant sterols. Phytosterols aren’t able to be used in humans (or other mammals).

It is estimated that people generally consume 200-400 mg/day of plant sterols, but that is going to vary widely depending on your diet (e.g. vegan vs carnivore vs mixed). A recent study found that vegans had the highest plant sterol intake and lowest cholesterol intake – and this was opposite from people eating an omnivore diet (low plant sterols, higher cholesterol). Interestingly, all the dietary pattern groups had similar blood cholesterol levels and sterol levels, showing that intake may not make much of a difference from the diet. [ref Trusted Source: Peer Reviewed Journal]

Plant sterols lower cholesterol levels:

Quite a few studies are showing in an average population group increasing plant sterols will decrease cholesterol levels.

The cholesterol-lowering effect in an average population increases as the dose of plant sterols increases – up to about 2 -3g/day. [ref Trusted Source: Peer Reviewed Journal] An intake of around 2g/day of plant sterols is associated with an average decrease in LDL cholesterol of about 10%. [ref Trusted Source: Peer Reviewed Journal]

Phytosterols reduced the intestinal absorption of cholesterol because they compete with cholesterol and block it. It is thought that this lower intestinal absorption includes both dietary cholesterol and the recycling of cholesterol in bile acids.[ref Trusted Source: Peer Reviewed Journal]

Phytosterols have also been associated with a reduction in triglycerides in patients with high triglyceride levels. [ref Trusted Source: Peer Reviewed Journal]

Do plant sterols reduce cardiovascular disease?

That is the big question…  and one that is not as well answered as I would like.

Some studies show that phytosterols reduce LDL and non-HDL cholesterol, which reduced arterial stiffness (important in cardiovascular health). [ref Trusted Source: Peer Reviewed Journal]  Margarine that contains rapeseed-sterols (canola) reduced cholesterol levels and also reduced E-selectin concentrations, which is a cellular adhesion molecule important in the arteries and atherosclerosis.[ref Trusted Source: Peer Reviewed Journal]

A long-term study of plant sterol consumption (2.5 g/day for 85 weeks) showed that LDL cholesterol dropped, but this didn’t have a significant effect (positive or negative) on smaller blood vessel function. The study didn’t include very many participants in it, which would make getting a significant effect difficult. [ref Trusted Source: Peer Reviewed Journal]

Could plant sterols have the opposite effect and increase the risk of cardiovascular disease?

Something that you don’t see mentioned in the marketing literature for plant sterols is the link with increased atherosclerosis and an increased risk of heart disease for some people, depending on their genetic variants.

There are really rare genetic mutations that cause a condition known as sitosterolemia. People with the rare mutations in the ABCG5 or ABCG8 genes absorb between 15 and 60% of phytosterols from their diet (compared with the normal 5% or so).  The ABC genes code for proteins known as ATP-binding cassette transporters, which move substances – in this case, phytosterols – out of the cell. ABCG5 and ABCG8 code for the proteins that make up the sterolin transporter that pumps the absorbed plant sterols back into the intestines.[ref Trusted Source: Peer Reviewed Journal] These transporters may also be important in moving cholesterol back into the intestines as well.

So what happens with high absorption of plant sterols in sitosterolemia? Atherosclerosis can start as early as childhood, and some people develop xanthomas, which are yellowish growths that contain cholesterol. People with sitosterolemia can also have joint pain and hemolytic anemia. [ref Trusted Source: Peer Reviewed Journal]

While the negative effects of building up high amounts of plant sterols are clear, the question remains whether this is a spectrum… is there a point that a person without a rare genetic mutation can have negative effects from a higher intake of plant sterols?

A study came out about 10 years ago, showing that higher levels of sitosterol and campesterol (the most common phytosterols) were linked to an almost doubled risk of cardiovascular disease. The study participants all had a similar dietary intake of macronutrients as well as omega-6 fatty acid levels. The study concluded overall increased absorption (cholesterol, plant sterols) was associated with cardiovascular disease. [ref Trusted Source: Peer Reviewed Journal]

Several other studies also claim that the link between elevated plant sterols and coronary artery disease is due to overall cholesterol absorption and alterations to endogenous production. [ref Trusted Source: Peer Reviewed Journal]

On the other hand, animal studies show that elevated plant sterols (stigmasterols), causes cardiovascular disease even while reducing LDL cholesterol.[ref Trusted Source: Peer Reviewed Journal]

It could be that a specific type of plant sterol or oxidation of plant sterols is what elevates cardiovascular disease. Patients with higher oxidized plant sterol levels had an increase in ‘cardiovascular events’. [ref Trusted Source: Peer Reviewed Journal]

Overall, the FDA, European Food Safety Authority,  and Health Canada have decided that food products with higher plant sterol levels can be labeled as being good for reducing cardiovascular disease.  [ref Trusted Source: Peer Reviewed Journal]  There was a nine-part study done that showed that plant sterol consumption is non-toxic and doesn’t cause cancer in animals. [ref ](Studies done by Unilever, manufacturer of products with plant sterols)


Genetics, Sterols, and Lowering Your Cholesterol:

Studies on plant sterols, stratified by genetic polymorphisms:

Variants that impact whether plant sterols lower cholesterol:

CYP7A1 gene: codes for an enzyme important in bile acid synthesis

Check your genetic data for rs3808607 (23andMe v4, v5; AncestryDNA):

  • T/T: no cholesterol-lowering benefit from plant sterols[ref Trusted Source: Peer Reviewed Journal]
  • G/T: plant sterols may help lower cholesterol
  • G/G: plant sterols may help lower cholesterol.

Variants that impact plant sterol effect on triglycerides:

CETP gene: codes for the cholesterol ester transfer protein

Check your genetic data for rs5882 (23andMe v4, v5; AncestryDNA):

  • A/A: no triglyceride lower effect from plant sterols [ref Trusted Source: Peer Reviewed Journal]
  • A/G: no triglyceride lower effect from plant sterols [ref Trusted Source: Peer Reviewed Journal]
  • G/G: plant sterols shown to lower triglycerides

Variants that impact whether more plant sterols are absorbed (CVD risk?):

ABCG8 gene: codes for part of the transporter that moves plant sterols from the intestinal cells back into the intestines for excretion. Some variants increase the absorption of plant sterols and some decrease the absorption of plant sterols. Where there is also research indicating an increase or decrease in cardiovascular disease (CVD), it is indicated as well.

Check your genetic data for rs41360247 (23andMe v4, v5; AncestryDNA):

  • T/T: typical (most common)
  • C/T: reduced phytosterol levels, somewhat reduced risk of coronary artery disease [ref Trusted Source: Peer Reviewed Journal]
  • C/C: reduced phytosterol levels, somewhat reduced risk of coronary artery disease [ref Trusted Source: Peer Reviewed Journal]

Check your genetic data for rs4245791 (23andMe v4, v5; AncestryDNA):

  • C/C: increased plant sterols, slightly increased CVD[ref Trusted Source: Peer Reviewed Journal][ref Trusted Source: Peer Reviewed Journal]
  • C/T: intermediate
  • T/T: typical (most common)

Check your genetic data for rs4148217 Thr400Lys (23andMe v4, v5; AncestryDNA):

  • C/C: typical
  • A/C: reduced risk of heart disease
  • A/A: reduced risk of heart disease [ref Trusted Source: Peer Reviewed Journal]

Check your genetic data for rs4299376 (23andMe v4, v5; AncestryDNA):

  • T/T: typical
  • G/T: increased risk of heart disease
  • G/G: increased risk of heart disease [ref Trusted Source: Peer Reviewed Journal] increased cholesterol and plant sterol absorption[ref Trusted Source: Peer Reviewed Journal]

Check your genetic data for rs11887534 D19H (23andMe v4 only):

  • G/G: typical
  • C/G: increased susceptibility to coronary artery disease (CAD); increased risk of gallstones,
  • C/C: increased susceptibility to CAD [ref]; greatly increased risk of gallstones[ref Trusted Source: Peer Reviewed Journal][ref Trusted Source: Peer Reviewed Journal]

Check your genetic data for rs137854891 (AncestryDNA only):

  • C/C: typical
  • C/G: carrier of a rare mutation for sitosterolemia
  • G/G: sitosterolemia (pathogenic)[ref Trusted Source: Peer Reviewed Journal]

Check your genetic data for rs199689137 (AncestryDNA only):

  • G/G: typical
  • A/G: carrier of a rare mutation for sitosterolemia
  • A/A: sitosterolemia (pathogenic)[ref Trusted Source: Peer Reviewed Journal]

Check your genetic data for rs119479065 (AncestryDNA only):

  • G/G: typical
  • A/G: carrier of a rare mutation for sitosterolemia
  • A/A: sitosterolemia (pathogenic)[ref Trusted Source: Peer Reviewed Journal]

Check your genetic data for rs137854891 (AncestryDNA only):

  • C/C: typical
  • C/G: carrier of a rare mutation for sitosterolemia
  • G/G: sitosterolemia (pathogenic)[ref Trusted Source: Peer Reviewed Journal]

Check your genetic data for rs137852987 (23andMe v4; AncestryDNA):

  • G/G: typical
  • A/G: carrier of a rare mutation for sitosterolemia
  • A/A: sitosterolemia (pathogenic)[ref Trusted Source: Peer Reviewed Journal]

ABCG5 gene: codes for the other part of the transporter that decreases the absorption of plant sterols

Check your genetic data for rs6720173 Q604E (AncestryDNA only):

  • G/G: typical
  • C/G: 4-fold greater decrease in LDL with plant sterol consumption[ref Trusted Source: Peer Reviewed Journal]
  • C/C: 4-fold greater decrease in LDL with plant sterol consumption[ref Trusted Source: Peer Reviewed Journal]

Lifehacks:

You should decide – based on your genetic variants – whether you think that increasing plant sterols is good for you. There seemed to be a lot of assumptions and biases (e.g. industry sponsorship) in some of the studies on phytosterols. To be perfectly honest, I don’t understand the nuances well enough to make a good judgment on which studies are skewing their data.

The research does seem to clearly show that for people with the normal CYP7A1 variant, increasing plant sterols to around 2g/day will decrease LDL cholesterol levels. If you were looking for a way to reduce LDL numbers before a blood test, this may work for you. The question, in my mind, is whether that decrease in LDL cholesterol makes a difference in cardiovascular disease risk (and whether long-term plant sterol supplementation would possibly increase CVD risk for some people).

Foods high in plant sterols:

Common foods that are high in phytosterols include oils (e.g. sunflower, canola, hemp, safflower, sesame, olive, cottonseed), avocados, raw peas, pistachios, cashews, macadamia nuts, and almonds. [ref][ref Trusted Source: Peer Reviewed Journal][ref Trusted Source: Peer Reviewed Journal]

Phytosterol enriched foods are also available for the consumer. They range from low-fat yogurt and milk to mayonnaise and chocolates.

Beta-sitosterol is available as a supplement and in foods such as the butter-alternative spreads that are marketed as containing plant sterols. (Read the rest of the ingredients, though, on the butter alternatives to make sure they are something you want in your diet.)More to read: ABCG5 and ABCG8: more than a defense against xenosterols

CYP2C8: Prescription medications and arachidonic acid

The CYP (cytochrome) family of genes codes for a number of different enzymes that interact with prescription drugs. This family of enzymes is important in breaking down medications in a process known as phase I detoxification. Genetic variants that alter the way that these enzymes work can impact your reaction to a medication.

The CYP2C8 gene is important in the metabolism of several chemotherapy drugs (e.g. Taxol) as well as playing a role in the metabolism of NSAIDs.

Here is a good list of drugs metabolized using CYP2C8 along with the other enzymes that can also play a role in their metabolism.  A database of pharmacological and genetic interactions has information on the CYP2C8 variants and response to tacrolimus, montelukast, rosiglitazone, and pioglitazone. More information can also be found in this publication.

In addition pharmaceutical drugs, CYP2C8 also metabolizes arachidonic acid in the body, which is important in blood pressure regulation. This may also be important in oxidative stress in the cell. [ref ]

The metabolism of arachidonic acid by CYP2C8 is also important in eye health in aging. Hypoxia, or low oxygen, increases CYP2C8, which in turn causes more of the conversion of arachidonic acid into epoxyeicosatrienoic acids (EETs). The increased EETs then promote abnormal vascular development in the retina of the eye. Additionally, the increased CYP2C8 also interacted with omega-3 fatty acids, also promoting abnormal vascular development with higher levels of DHA in low oxygen conditions. [ref ]

Inhibiting CYP2C8 has been shown in studies to decrease the pathological effects in the eye from increased vascular development. This could be important in age-related macular degeneration and diabetic retinopathy. [ref ]  Please keep in mind that you don’t want to inhibit CYP2C8 if you are on a prescription medication that relies on the enzyme.


Genetic Variants in CYP2C8:

There are genetic variants that occur in the CYP2C8 gene that impact how the enzyme functions.

Check your genetic data for rs10509681 (23andMe v4, v5; AncestryDNA):

  • C/C: CYP2C8*3, decreased enzyme function[ref ]; ibuprofen takes longer to be metabolized [ref ]; increased risk of GI bleeding with NSAIDs [ref ], increased risk of neuropathy in breast cancer patients treated with paclitaxel[ref ]
  • C/T: one copy of CYP2C8*3, decreased enzyme function; increased risk of GI bleeding with NSAIDs
  • T/T: normal

Check your genetic data for rs11572103 (23andMe v4, v5; AncestryDNA):

  • A/A: CYP2C8*2; decreased enzyme function[ref ]
  • A/T: one copy of CYP2C8*2; decreased enzyme function[ref ]
  • T/T: normal

Check your genetic data for rs1058930 (23andme v4, v5; AncestryDNA):

  • C/C: CYP2C8*4; slightly decreased enzyme function[ref]
  • C/G: one copy of CYP2C8*4; slightly decreased enzyme function
  • G/G: normal

Check your genetic data for rs7909236 (23andMe v4; AncestryDNA):

  • T/T: CYP2C8*1B; increased enzyme activity [ref] increased risk of hypertension[ref ]
  • G/T: one copy of CYP2C8*1B; increased enzyme activity [ref]
  • G/G: normal

Lifehacks:

If you carry the CYP2C8*3 variant and take a lot of NSAIDs, you should seriously talk with your doctor about the increased risk of GI bleeds.

Quercetin, a flavonoid that is often used as an anti-inflammatory supplement, is an inhibitor of CYP2C8.[ref ] If you carry a genetic variant that slows CYP2C8 plus take quercetin along with a medication that uses CYP2C8, the interaction could cause the medication not to work appropriately.

Circling back around to the information above on how upregulation of CYP2C8 could increase problems with the retina, such as macular degeneration or diabetic retinopathy…  Quercetin, an inhibitor of CYP2C8, has been shown to protect the eye from damage from diabetic retinopathy in animal studies. [ref ]  This may be something to consider if on a diet that is high in the long-chain omega-6 or omega-3 fatty acids, especially if AMD or diabetic retinopathy is a concern.

More to read:
Check out your other CYP450 genetic variants: Phase I and Phase II Detoxification

 

Uterine fibroids

Uterine fibroids are a problem for a lot of women, especially after age 30. Fibroids are benign tumors that grow in the muscle cells of the uterus. While estimates vary, at least half of American women who are of reproductive age have fibroids. [ref ]

This article will dig into the causes of fibroids, explain how your genetic variants can add to the susceptibility, and offer solutions that are backed by research.

Uterine fibroids:

Symptoms of fibroids include:

  • painful or heavy periods
  • anemia
  • frequent need to urinate
  • painful sex
  • low back pain

Fibroids can also play a role in infertility for some women. But not all women have symptoms with fibroids – it depends on the location and size.

Fibroids are also known as uterine leiomyoma, which means smooth muscle tumor.

Causes of fibroids

You would think that something that affects more than half of women would be well understood and have good solutions available. Oddly enough, there are still questions surrounding the causes of fibroids, and a lot of the solutions available are either ineffective or come with significant side effects.

Genetics plays a role in the susceptibility to fibroids, but, as you will see,  lifestyle factors are also important. [ref ]

Stem cells and growth

Fibroids are medically classified as benign tumors, which means that they are nearly always non-cancerous growths.

Genetics studies show that a fibroid will arise from one cell that has somewhat unchecked growth. Stem cells are present in the muscle of the uterus, which needs to be able to grow and change both monthly and in pregnancy.  [ref ][ref ]

The stem cells in the uterine muscle are capable of replicating into more muscle tissue – that is their whole purpose. When there is DNA damage in a growth related gene, the stem cell to go on a growth spree and become a fibroid. Additionally, the conditions for growth and proliferation of the cell need to be right (see below). The body’s normal way of dealing with damaged DNA also needs to be overridden. [ref ]

Estrogen, progesterone, and growth

Estrogen and progesterone are involved in the formation and growth of fibroids, which occurs mainly during the reproductive years when estrogen and progesterone levels are high. Fibroids usually decrease in size once a woman reaches menopause.

The cells in a fibroid have increased estrogen and progesterone receptors. Animal studies show that the addition of estrogen alone, or estrogen plus progesterone, can increase the size of fibroids.[ref ]

In the uterus, estrogen upregulates IFG-1 (insulin-like growth factor 1), EGFR, TGF-beta1.  All of these are growth-related molecules. [ref ]

Interleukin-1 is an inflammatory cytokine that can inhibit REST, which is a tumor suppressor. Interleukin-1 is also upregulated in fibroid tissue. [ref ]

Environmental exposure

Adding fuel to the fibroid fire, exposure to endocrine-disrupting chemicals such as BPA and phthalates also increases the risk and growth of fibroids.

BPA is a component of plastics and a known endocrine disruptor, similar in structure to estrogen. A cell study shows that exposure to low levels of BPA increases the proliferation of fibroid cells. [ref ] A study of 495 women who were diagnosed with fibroids found that they had higher concentrations of BPA in them than women without fibroids.[ref ]

2-hydroxy-4-methyoxybenzophenone, a UV filter found in sunscreens, is also linked to an increase in fibroids. [ref ]

Phthalates, which are found in plastics, vinyl, and fragrances, are also endocrine-disrupting chemicals that are linked with an increased risk of fibroids. This was especially true in women who carry the GSTM1 null genotype.[ref ]

In-utero and infant exposures:

Early-onset fibroids are linked with exposure to diethylstilbestrol (DES) in-utero. DES is an estrogen medication that was used from 1940 to 1971 for pregnant women. The daughters of women who took DES were at a higher risk of fibroids and at a younger age.  [ref ]

Infectious agents:

Infection with cytomegalovirus in the uterine tissue is associated with a 6-fold increase in the risk of fibroids. On the other hand, Chlamydia trachomatis decreased the risk of fibroids. [ref ][ref ]


Genetic variants that increase the risk of fibroids:

None of these genetic variants cause fibroids on their own. Instead, they all add to the susceptibility. You will notice that these variants are involved in the vascular system (important for blood vessels for the fibroid), DNA repair pathways (important in proliferation), and estrogen pathways.

ACE gene: codes for the angiotensin-converting enzyme which is important in vascular diseases.

Check your genetic data for rs4343  (23andMe v4, v5; AncestryDNA):

  • A/A: normal (ACE insertion/insertion)
  • A/G: increased risk of fibroids (ACE deletion/insertion)
  • G/G: increased risk of fibroids (ACE deletion/deletion)

XPC gene: codes for part of the DNA repair pathway

Check your genetic data for rs2228000 (23andme v4, v5; AncestryDNA):

  • G/G: normal risk of fibroids
  • A/G: decreased risk of fibroids
  • A/A: decreased risk of fibroids[ref ]

XPG gene: codes for part of the DNA repair pathway

Check your genetic data for rs873601 (23andMe v5; AncestryDNA):

  • A/A: increased risk of fibroids [ref ]
  • A/G: normal risk of fibroids
  • G/G: normal risk of fibroids

CYP1B1 gene: estrogen metabolism

Check your genetic data for rs1056827 A119S (23andMe v4 only):

  • C/C: normal
  • A/C: somewhat increased risk of uterine fibroids
  • A/A: increased risk of breast cancer [ref ] increased risk of uterine fibroids [ref ]

ESR1 gene: estrogen alpha receptor1

Check your genetic data for rs2234693 Pvull (23andMe v4, v5; AncestryDNA):

  • T/T: slightly lower risk of fibroids [ref ]
  • C/T: normal risk of fibroids
  • C/C: normal risk of fibroids

CCND1 gene: cell cycle regulatory protein

Check your genetic data for rs9344 (AncestryDNA only):

  • G/G: normal risk of fibroids
  • A/G: slightly increased risk of fibroids
  • A/A: increased risk of fibroids[ref ]

FASN gene: fatty acid synthase

Check your genetic data for rs4247357 (23andMe v4; AncestryDNA):

  • T/T: increased risk of fibroids [ref ]
  • G/T: increased risk of fibroids
  • G/G: normal risk of fibroids

GSTM1 gene: glutathione-S transferase, part of phase II detoxification

Check your genetic data for rs366631 (23andMe v4 only):

  • A/A: deletion (null) GSTM1 gene. Five-fold increased risk of fibroids with higher phthalate exposure [ref ] (This is actually the most common genotype in most populations.)
  • A/G: GSTM1 present
  • G/G: GSTM1 present

 


Lifehacks for fibroids:

Dietary associations:

Women eating more than 2 servings of fruits in a day had a slightly decreased risk of uterine fibroids compared to women eating less than 2 servings per week.  A higher intake of animal sources of vitamin A was also linked to a slightly decreased risk of uterine fibroids.[ref ]

Another study found that frequent milk and soybean use was linked with an increased risk of fibroids.[ref ] Unfortunately, the study lumped both of those together as a category, so I’m not sure which one was important. The implication here is that additional phytoestrogens or bovine hormones could increase fibroids.

Food additives, sweeteners, and preserved foods have also been linked to an increased risk of fibroids. (Not really helpful since the study doesn’t really narrow down or define those terms.) [ref ]

Oral contraceptive use is linked to an increased risk of fibroids.[ref ] Alternatively, some types of oral contraceptives can also be used to slow menstrual bleeding and decrease the symptoms of fibroids.

Flavonoids:

The fact that increased fruit intake and decreased preserved foods are linked to fewer fibroids leads one to think that natural polyphenols in fruits and vegetables may be good for fibroids.

EGCG:  A randomized controlled trial of green tea extract (800 mg, 45% EGCG) found that the women consuming the green tea extract had a reduction in fibroid size and a decrease in blood loss. The women in the placebo arm of the trial had an increase in fibroid size.  [ref ] You can get green tea extract on Amazon or at your local health food store. Be sure to read the label to determine the amount and percentage EGCG.

Kaempferol is a flavonoid that has been shown in cell culture studies to inhibit the proliferation of fibroid cells.  It also decreased IGF1 and VEGF, both of which are thought to be involved in the growth of fibroids. [ref ]

Resveratrol has been shown in a cell study to reduce the growth of fibroids. [ref ]

Curcumin has also been shown in tissue studies to stop the growth of fibroid tissue.[ref ]

Avoid phthalates and BPA:

Phthalates are a chemical found in plastics, vinyl, and artificial fragrances (personal care products, air fresheners, and laundry products). They act as estrogen mimics in the body. The level of phthalate metabolites is associated with the size of fibroids – more phthalates in the body = bigger fibroids. [ref ][ref ]

Similarly, higher BPA levels have also been linked with increased odds of fibroids. BPA can be found in some plastics, household dust, and thermal printed receipts.

What can you realistically do to avoid phthalates and BPA? Check your personal care products for phthalates, and look for laundry products without artificial fragrances included. Dusting and vacuuming regularly has been shown to decrease BPA. Handling thermal printed receipts, especially with wet hands, has been shown to increase BPA fairly significantly in the body.

NSAIDs and aspirin:

While not without potential long-term side effects drawbacks, using anti-inflammatory drugs, such as ibuprofen, can be effective for reducing heavy menstrual flow.  [ref ] Aspirin has been shown in cell studies to reduce fibroid proliferation. [ref ]

 


Related Genes and Topics:

Thyroid Genes: Autoimmunity and Hypothyroidism
The thyroid is a master regulator of many of your body’s systems. It is integrally involved in metabolism and helps maintain body temperature, heart rate, breathing, and body weight. Your genes play a big role in how well your thyroid works and how your body produces and converts the different forms of thyroid hormone.