Genetic basis for POTS: Getting to the Root Cause

Do you feel lightheaded when you stand? Does your heart suddenly race? POTS (postural orthostatic tachycardia syndrome) is a problem with the way that your autonomic nervous system regulates heart rate. POTS causes more than just feeling lightheaded when standing —  it can also cause fatigue, brain fog, shaking, and more.

There are multiple triggers or root causes of this syndrome, and genetic variants can increase your risk for POTS.

 

Postural Orthostatic Tachycardia Syndrome (POTS)

Doctors define POTS as:

  • an increase of heart rate of 30 BPM (beats per minute) within the first 10 minutes of standing
  • Or, an increase of heart rate to over 120 BMP within the first 10 minutes of standing[ref]

These requirements define POTS as long as the person doesn’t have orthostatic hypotension (a condition where blood pressure initially drops when standing).

For teens and kids, most doctors now define POTS as being a heart rate increase of over 40 BPM.

Millions of people around the world have POTS. The Dysautonomia International website explains that POTS impacts 1 to 3 million Americans.

POTS Symptoms:

Symptoms that often go along with POTS include[ref][ref][ref][ref]:

  • fatigue
  • headaches, brain fog
  • lightheaded, fainting, vertigo
  • heart palpitations, chest pain
  • exercise intolerance
  • shaking, cold hands and feet
  • abdominal pain, nausea, bloating
  • diarrhea, constipation, bladder problems

Cause of POTS (Postural Orthostatic Tachycardia Syndrome):

POTS is a syndrome – meaning a collection of symptoms – rather than a specific disease. Thus there are a variety of diseases or chronic conditions that can cause POTS symptoms.

Diseases and conditions linked to triggering POTS include:

  • Autoimmune activation of the adrenergic system[ref][ref]
  • Autoimmune activation of the angiotensin II type 1 receptor[ref]
  • Mast cell activation[ref]
  • Viral illness, infections[ref][ref]
  • Joint hypermobility (found in about 50% of teens with POTS), Ehlers Danlos[ref][ref]
  • linked to HPV vaccine (more studies are needed on this to show causality)[ref]
  • Concussions[ref]
  • Surgery, bed rest[ref]
  • Inflammatory disorders[ref]

POTS is often worsened by heat stress.

Going from lying down to standing up: blood pressure and heart rate

When someone who does not have POTS goes from laying in bed to standing up, there are a bunch of regulatory things that go on in the body. The blood pressure and heart rate regulation are automatic, and we don’t even notice that it happens.

Upon standing, gravity causes blood to go from the chest to the lower abdomen and legs. Within the first 30 seconds of standing, there is a fluid shift, between the blood vessels and the space in between the cells. This change in blood volume causes receptors in the heart to be activated and alters the stroke volume of the heart. All of this causes the heart rate to normally increase just a little bit. It also alters blood pressure (decreased systolic BP and increased diastolic BP) just a bit.[ref]

This is all normal – a slight increase in heart rate and BP.

What happens when a person with POTS stands up?

There are a couple of different scenarios of what is happening in people with POTS (more details below). But generally, POTS can be caused by low blood volume or by the blood vessels in the legs not constricting enough.[ref]

If the person with POTS is hypovolemic – reduced blood volume – they usually have an elevated heart rate even when at rest. This is worsened upon sitting or standing, and the heart rate increases substantially.

For someone with reduced vasoconstriction in the legs, the heart rate increases dramatically to maintain normal blood pressure. This could be worsened in conditions of high heat causing more blood to flow to the skin.[ref]

Autonomic nervous system, blood regulation:

Dysautonomia is a term you will often see when reading about POTS. Essentially, dysautonomia means that there is a dysfunction of the autonomic nervous system. It is kind of a catch-all term, with several chronic conditions falling under the umbrella of dysautonomia.[ref]

The autonomic nervous system controls involuntary functions in the body – including heart rate, blood pressure, and the motility of the digestive tract.

The body tightly regulates blood pressure through the renin-angiotensin-aldosterone system. It balances out the volume of blood through regulating sodium. In the kidneys, this system can either increase sodium reabsorption or water reabsorption to alter the volume of blood in the body.[ref] (Think about osmosis from science class — changing the amount of water through a membrane due to how much salt is on one side of the membrane. The kidneys regulate sodium concentration to regulate fluid in this same way.)

Angiotensin system and POTS: When the renin-angiotensin-aldosterone system is involved in causing POTS, there can be an increase in plasma angiotensin II. This causes an imbalance of blood volume due to the kidneys not retaining enough sodium. Additionally, some researchers have found that there is inadequate ACE2 activity.[ref][ref]

Vasoconstriction and POTS: Some people with POTS have problems with the sympathetic nervous system not working correctly in the feet and legs. This can result in not enough vasoconstriction (e.g. blood vessels are too relaxed) when standing up. Thus blood pools in the legs/feet and in the abdominal cavity. The lack of vasoconstriction and the pooling blood then kicks the heart into high gear, pumping hard to make up for lack of blood flow.[ref]

Sympathetic nervous system, NET, medications, and POTS:

One branch of the autonomic nervous system is the sympathetic nervous system (fight or flight response). Norepinephrine (aka noradrenaline) functions in the body as a neurotransmitter and as a stress hormone. The activation of the sympathetic nervous system releases norepinephrine.

Adrenergic system and POTS: Another subset of people with POTS have what is known as the ‘hyperadrenergic’ form. For these people, their body releases excess norepinephrine when standing. This can cause heart palpitations, tremors, rapid heartbeat, feeling anxious, and an increase in blood pressure. Some patients with hyperadrenergic POTS also get headaches upon standing.[ref][ref]

Alternatively, the body can also not clear out the normal norepinephrine quickly enough.

Norepinephrine transporter: Alterations in the norepinephrine transporter (NET) can cause reduced clearance of norepinephrine, leaving the sympathetic nervous system in a state of excessive activation. Rare mutations and more common variants in the gene that codes for NET (norepinephrine transporter) are linked to POTS. Additionally, certain medications are NET inhibitors – some tricyclic antidepressants and certain ADHD medications [ref]

For example, atomoxetine (Strattera) is an ADHD medication that targets the norepinephrine transporter. In a clinical trial, it has shown to significantly increase the standing heart rate in POTS patients.[ref]

Autoimmunity causing POTS:

So what could cause either the regulation of blood volume or the adrenergic (norepinephrine) system to go haywire?

Research has shown that for a lot of people, POTS can be due to an autoimmune attack on either the adrenergic system or the renin-angiotensin system.[ref][ref] Both of these systems are important in heart rate and blood flow.

For example, a small study in 2018 found that most patients with POTS in their study had angiotensin II type 1 receptor antibodies (IgG) as well as adrenergic activation, showing an autoimmune activation of that receptor. Interestingly, losartan, a commonly used hypertension medication that acts on the angiotensin II receptor, was able to reduce the receptor activity down to the same levels as control.[ref]

Another recent study (Aug. 2020) showed that the patients with POTS were very likely to have autoimmune activity towards the adrenergic receptors1 receptor,  β2 receptor, cholinergic, and opioid receptor-like 1).[ref]

Genetics and Epigenetics:

Genetic mutations and POTS: There is no one specific gene mutation that causes POTS. Rather, POTS is a syndrome that can have its genetic roots in a variety of different genes. Understanding where your genetic susceptibility lies may help you find your best treatment options.

For many people, an autoimmune condition (adrenergic system, angiotensin II receptor) triggers POTS.

The HLA genes code for an important part of our adaptive immune system. They help the body to understand what is foreign (bacteria, virus) and needs to be attacked. They also help the body understand which tissue is ‘self’ and should be left alone by the immune system.

Quite a few autoimmune diseases are linked to having different variants in the HLA genes.  This HLA gene variation makes the human population resilient to lots of different and new pathogens, but this variation also makes individuals more susceptible to autoimmune disease.

One of the biggest risk factors, though, is and HLA variant that is not included in 23andMe or AncestryDNA data. A study in 2019 identified the HLA-DQB1*0609 serotype as increasing the risk of POTS by over 8-fold![ref]

Other genetic variants increase susceptibility to POTS in different ways. (see the Genetic Variants section below).

Epigenetics and POTS: Epigenetics refers to alterations in how the genetic code is turned on or off for translation. In a nutshell, the nucleus of every cell contains the complete genome, but only certain genes remain essential for that cell to function.

Studies showed that people with POTS were more likely to have epigenetic modifications that reduced the function of the norepinephrine transporter (SLC6A2 gene).[ref][ref] This goes hand-in-hand with the research showing that people with genetic variants that reduce the function of the SLC6A2 gene are also more susceptible to POTS. (See genetics section below).

Vaccines and POTS:

One trigger for POTS for some individuals seems to be certain vaccines.  For example, there are dozens of case reports of POTS shortly following the HPV vaccine.  Additionally, several studies followed a number of women after the HPV shot, finding an increase in dysautonomia and POTS.[ref][ref][ref][ref][ref]

Why would an HPV vaccine cause POTS in a minority of people? Some researchers point to an autoimmune response (adrenergic receptor antibodies) due to molecular mimicry with specific HPV peptides.[ref]

There is, of course, a lot of unanswered questions on the links between the HPV vaccine and POTS. Epidemiological studies often don’t find a statical population-wide link between the introduction of the HPV virus and the number of POTS diagnoses.[ref][ref] Additionally, some researchers point to media coverage as a cause for any post-vaccination symptom spikes.[ref]

SARS-CoV-2 and POTS:

Interestingly, one of the mechanisms that cause POTS is a disturbance in the renin-angiotensin system that could be due to inadequate ACE2 activity.[ref] A study of 38 people with POTS had lower ACE2 activity than in the healthy control group.[ref]

Researchers have recently discovered (Aug. 2020) that the SARS-CoV-2 may cross-react with autoimmune target proteins. The researchers caution that people who have had the SARS-CoV- virus may be at an increased risk for autoimmune conditions.[ref]

Will there end up being an increase in POTS from the SARS-CoV-2 virus? We need more research (and time) to know the answer here.


Genetic Variants Linked to POTS:

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Below are several genetic variants that are linked to an increased (or decreased) susceptibility to POTS.

These genes don’t cause POTS by themselves, but instead, the variants cause an increased risk that combines with an environmental trigger which results in the syndrome.

SLC6A2 gene: codes for a norepinephrine transporter (NET), which removes norepinephrine from the junction between sympathetic nerves. NET impairment is linked to depression, panic disorder, tachycardia, and POTS. [ref]  Rare mutations (not covered here) in the SLC6A2 gene have also been linked to POTS.

Check your genetic data for rs7194256 (23andMe v5 only):

  • C/C: typical
  • C/T: increased risk of POTS; increased arterial norepinephrine, depression, and anxiety scores, larger left ventricular mass index, higher systolic and diastolic blood pressures, and heart rate
  • T/T: increased risk of POTS; increased arterial norepinephrine, higher depression, and anxiety scores, larger left ventricular mass index, higher systolic and diastolic blood pressures, and heart rate.[ref]

Members: Your genotype for rs7194256 is .

 

GNB3 gene:  codes for a subunit of a G-protein that is involved in signal transduction, thus it can impact a lot of systems in the body including metabolism and blood pressure. Specifically, in relation to POTS, this variant causes “enhanced vagal withdrawal of the heart”.[ref]

Check your genetic data for rs5443 (23andMe v4, v5; AncestryDNA):

  • C/C: best mood, least hunger
  • C/T: lower heart rate laying down, larger increase standing up
  • T/T: lower heart rate laying down, larger increase standing up, 2-fold greater risk of POTS [ref]

Members: Your genotype for rs5443 is TT.

 

NOS3 gene: code for endothelial nitric oxide (NO) synthase enzyme, which is essential for relaxing blood vessels. NO production helps to regulate blood flow. Other NOS3 variants, not included in 23andMe or AncestryDNA data, are also linked to POTS.

Check your genetic data for rs2070744 (23andMe v4, v5 only):

  • T/T: common variant, (higher risk of pots)
  • C/T: higher risk of POTS compared to C/C
  • C/C: much less likely to have POTS [ref]

Members: Your genotype for rs2070744 is .

 

ADRB2 gene: codes for the beta2-adrenergic receptor

Check your genetic data for rs1042713 (23andMe v4, v5; AncestryDNA):

  • G/G: typical
  • A/G: typical response to tilt-table
  • A/A: increased heart rate on tilt-table, increased norepinephrine in response to tilt-table [ref]

Members: Your genotype for rs1042713 is .

 


Lifehacks for POTS:

Decreasing POTS symptoms:

Increased your fluid intake
Hypovolemia, or lower levels of blood volume, may be helped, in part, by increasing the amount of water – or electrolyte sports drink – that you consume.[ref]

Increased sodium intake.
Similar to increasing fluid intake, if your sodium intake is low or your electrolyte balance is off, it can affect blood volume.  Often, people with POTS are encouraged to drink sports drinks such as Gatorade.

Compression socks:
If your blood is pooling in your extremities, wearing compression socks can help.

Mast cell activation and POTS:
Check out the full article on mast cell activation syndrome along with the lifehacks section there.

Diet and Supplements:
The recommendations and studies seem to vary a lot on specific dietary interventions (e.g. some caffeine constricts the blood vessels, but caffeine worsens POTS for others).  Overall, a healthy diet with fresh vegetables and fruits, fish, and/or grass-fed meat should help to meet your needs for vitamins.

One study noted that teens with POTS were about 3 times more likely to have low vitamin B12 levels.[ref] Good food sources of B12 include liver, fish, meat, poultry, eggs, and dairy products.

Another study found that a (small) percentage of POTS patients had vitamin B1 (thiamine) deficiency and supplementing with B1 resolved POTS symptoms.[ref]

Low iron or low vitamin D are also linked to an increased risk for POTS in teens.[ref][ref] Both iron and vitamin D levels can be easily checked with a quick blood test. You can order tests yourself online (e.g. UltaLab tests) or through your doctor.

Cautious exercise:
People with POTS are often ‘deconditioned’ due to fatigue and not being able to exercise. Researchers recommend mild to moderate exercise in short periods several times a week in order to reverse the deconditioning.[ref] Talk with your doctor to figure out a plan that will work best for you.

There’s an app for that (POTS and Heart Rate Apps):

Several different heart rate apps are available for both Android and iPhone. There are even apps, such as Cardiogram, that integrate with Apple Watch for tracking heart rate.

The app called Instant Heart Rate includes a nice ‘standup test’ feature to see how much your heart rate increases when standing. The one thing that I don’t like about the app is that you have to create an account (which means the company is tracking your info).

Things to talk with your doctor about:

Beta-blockers are commonly prescribed for POTS and seem to work for some people. Beta-blockers work on the beta-2 adrenergic receptor. Logically, they may be more effective for people with POTS who have the ADRB2 variant (above) or for people who have an autoimmune reaction to the beta2-adrenergic receptor.

Losartan, an angiotensin II receptor blocker, may also be something to talk with your doctor about. Several studies show that it could be effective for some individuals with POTS if they have autoimmune activation of the angiotensin II receptor.[ref][ref][ref]

There is new research out showing that there may be ways to reverse the epigenetic changes that suppress the norepinephrine transporter.[ref] This research may be something to discuss with your doctor.


Related Genes and Topics:

How do your genes influence your vitamin B12 levels? (members article)
Vitamin B12 is essential for your health! It is a cofactor for biological reactions such as creating the myelin sheath in nerve cells and the synthesis of DNA (rather important!).

HLA-B27: Genetic Variant That Increases Susceptibility to Autoimmune Diseases

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.



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