Hypertension Risk Factor: CYP11B2 Variant

A regular heartbeat with blood just swooshing along, all day and night, is something that we take for granted. But the body’s regulation of blood pressure is truly complex and involves the heart, blood vessels, and kidneys. Aldosterone is a key player working to balance blood volume through kidney function.

Here we dig into one key enzyme, aldosterone synthase, which impacts blood pressure. Genetic variants in the aldosterone synthase gene increase the risk of high blood pressure and stroke.

What is aldosterone synthase?

CYP11B2 gene encodes aldosterone synthase, an enzyme involved in the biosynthesis of aldosterone.

First, what’s aldosterone? Aldosterone is a steroid hormone that regulates blood pressure and plasma sodium and potassium levels. It works on the kidneys to balance out electrolytes (Na+ and K+) as a way of influencing blood pressure and blood volume.

In the body, think of ‘water follows sodium’. We all know a meal high in salt can leave us feeling ‘puffy’ and the action here is of the same concept. Aldosterone influences the kidneys to retain sodium while also excreting potassium. This shift in the electrolyte balance that allows for sodium retention directly increases water retention…by water following sodium. The result of this action allows for an increase in blood volume and pressure.[ref]

RAAS pathway. CC image from Merck Manuals

Aldosterone synthase is produced in the adrenal cortex and regulated by the RAAS pathway (renin-angiotensin-aldosterone system). As the limiting factor in the production of aldosterone, the aldosterone synthase enzyme is crucial for both blood pressure regulation and electrolyte balance.

To form aldosterone, the enzyme aldosterone synthase catalyzes a reaction involving deoxycorticosterone in a multistep process to form aldosterone. Deoxycorticosterone is a steroid hormone produced by the adrenal glands, and it can also regulate potassium, similar to aldosterone. The key, though, is that deoxycorticosterone doesn’t usually decrease sodium levels very much in comparison to potassium.

The precursor for deoxycorticosterone (and thus, aldosterone) is progesterone. The hormone progesterone is synthesized in the body from cholesterol.

What does high aldosterone cause?

High aldosterone is linked to:[ref][ref][ref]

  • high blood pressure
  • stroke
  • headaches, fatigue (related to low potassium known as ‘hypokalemia’)
  • osteoporosis

Related Article: Osteoporosis Genes and Prevention Strategies

What does really low aldosterone cause?

Lack of aldosterone, often found in Cushing’s disease, is linked to salt-wasting, growth retardation in children, and failure to thrive. Altered potassium levels and low blood pressure can also occur.[ref][ref]


Genetic variant in CYP11B2:

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Check your genetic data for rs1799998 (23andMe v5; AncestryDNA):

  • A/A: typical
  • A/G: slightly increased heart disease risk[ref]
  • G/G: increased relative risk of hypertension in many different population groups (but not all)[ref][ref][ref][ref]; increased relative risk of stroke[ref][ref]; increased risk of a-fib[ref]; higher relative risk of pre-eclampsia[ref] possibly a better response to angiotensin II receptor blocker drugs[ref][ref]

Members: Your genotype for rs1799998 is .

 

Rare mutations in the CYP11B2 gene are linked to aldosterone synthase deficiency.

Check your genetic data for rs61757294 (AncestryDNA):

  • G/G: rare mutation for aldosterone synthase deficiency[ref]
  • A/G: carrier of a rare mutation for aldosterone synthase deficiency
  • A/A: typical

Members: Your genotype for rs61757294 is .

Check your genetic data for rs104894072 (23andMe v5; AncestryDNA):

  • G/G: rare mutation for aldosterone synthase deficiency[ref]
  • T/G: carrier of a rare mutation for aldosterone synthase deficiency
  • T/T: typical

Members: Your genotype for rs104894072 is .

Check your genetic data for rs28931609 (23andMe v4, v5):

  • G/G: typical
  • A/G: carrier of a rare mutation for aldosterone synthase deficiency
  • A/A: rare mutation for aldosterone synthase deficiency[ref]

Members: Your genotype for rs28931609 is .


Lifehacks:

People with hypertension along with the G/G genotype for rs1799998 may respond well to certain blood pressure-reducing drugs ending in -sartans. The -sartan drugs are angiotensin II receptor blockers.[ref][ref] These agents block the action of angiotensin II thus causing vasodilation and increased sodium and water excretion. (Talk with your doctor, of course!)

Aldosterone synthase inhibitors are a new class of hypertensive drug that is under development. Inhibiting CYP11B2 decreases aldosterone and subsequently increases deoxycorticosterone, thus changing sodium-potassium balance.[ref]

Another way that is being investigated for reducing aldosterone is to stop the stimulation of aldosterone in the adrenals. Substance P binds to a receptor to increase aldosterone synthase and blocking that receptor with drugs (in clinical trials) reduced aldosterone.[ref] If Substance P sounds familiar, it is a neuropeptide that is released in pain, vomiting, and hot flashes. In the adrenal glands, substance P partly influences aldosterone stimulation.

Sodium bicarbonate mineral water reduces aldosterone. The water used in one study contained 2g of bicarbonate per liter of water.[ref][ref]

Stress increases aldosterone.[ref] This is one of the ways that stress increases blood pressure.[ref]


Related Articles and Genes:

Heart Health Topic Summary
Utilize our Heart Health Topic Summary Reports with your 23andMe or AncestryDNA genetic data to see which articles may be most relevant to you. These summaries are attempting to distill the complex information down into just a few words. Please see the linked articles for details and complete references. (Member’s article)

High blood pressure due to AGTR1 gene variants
Blood pressure may not be something that you think much about – unless your doctor is harping about it being high or low. The CDC statistics, though, make a pretty compelling argument that a lot of us should be thinking about blood pressure. It is estimated that ~ 1/3 of US adults have high blood pressure, which contributes to more than 410,000 deaths each in the US in a year.

LDL Cholesterol Genes
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. Learn how your genes impact LDL levels.

BMAL1’s impact on the “Big 3”: heart disease, cancer, and diabetes
A core circadian rhythm gene, BMAL1, influences heart disease risk, diabetes, and cancer. Check your genes and learn how to mitigate the risk.

References:

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Azimi-Nezhad, Mohsen, et al. “Association of CYP11B2 Gene Polymorphism with Preeclampsia in North East of Iran (Khorasan Province).” Gene, vol. 733, Apr. 2020, p. 144358. PubMed, https://doi.org/10.1016/j.gene.2020.144358.
Azizi, Michel, et al. “Aldosterone Synthase Inhibition in Humans.” Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association – European Renal Association, vol. 28, no. 1, Jan. 2013, pp. 36–43. PubMed, https://doi.org/10.1093/ndt/gfs388.
“Figure: Regulating Blood Pressure: The Renin-Angiotensin-Aldosterone System.” Merck Manuals Consumer Version, https://www.merckmanuals.com/home/multimedia/figure/cvs_regulating_blood_pressure_renin. Accessed 20 Sept. 2021.
Gideon, Angelina, et al. “Kinetics and Interrelations of the Renin Aldosterone Response to Acute Psychosocial Stress: A Neglected Stress System.” The Journal of Clinical Endocrinology and Metabolism, vol. 105, no. 3, Mar. 2020, p. dgz190. PubMed, https://doi.org/10.1210/clinem/dgz190.
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Gorini, Stefania, et al. “Mineralocorticoid Receptor and Aldosterone-Related Biomarkers of End-Organ Damage in Cardiometabolic Disease.” Biomolecules, vol. 8, no. 3, Sept. 2018, p. 96. PubMed Central, https://doi.org/10.3390/biom8030096.
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—. “Renin-Angiotensin-Aldosterone System Gene Polymorphisms and Coronary Artery Disease: Detection of Gene-Gene and Gene-Environment Interactions.” Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology, vol. 29, no. 3–4, 2012, pp. 443–52. PubMed, https://doi.org/10.1159/000338498.
Kurland, Lisa, et al. “Aldosterone Synthase (CYP11B2) -344 C/T Polymorphism Is Related to Antihypertensive Response: Result from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) Trial.” American Journal of Hypertension, vol. 15, no. 5, May 2002, pp. 389–93. PubMed, https://doi.org/10.1016/s0895-7061(02)02256-2.
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Munshi, Anjana, et al. “Association of the −344C/T Aldosterone Synthase (CYP11B2) Gene Variant with Hypertension and Stroke.” Journal of the Neurological Sciences, vol. 296, no. 1, Sept. 2010, pp. 34–38. ScienceDirect, https://doi.org/10.1016/j.jns.2010.06.013.
Peter, M., et al. “Hereditary Defect in Biosynthesis of Aldosterone: Aldosterone Synthase Deficiency 1964-1997.” The Journal of Clinical Endocrinology and Metabolism, vol. 82, no. 11, Nov. 1997, pp. 3525–28. PubMed, https://doi.org/10.1210/jcem.82.11.4399.
“PharmGKB.” PharmGKB, https://www.pharmgkb.org/clinicalAnnotation/1183614600. Accessed 20 Sept. 2021.
“—.” PharmGKB, https://www.pharmgkb.org/clinicalAnnotation/1183614600. Accessed 20 Sept. 2021.
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Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.