PCSK9 Gene: Understanding the variants that cause high or low LDL cholesterol

Just over fifteen years ago, researchers discovered that a mutation in the PSCK9 gene caused really high cholesterol levels. This led to more discoveries about the gene and fast-tracked the development of medication for people with hypercholesterolemia.[ref]

This article looks at the PCSK9 genetic variants that are associated with either increased or decreased LDL cholesterol — along with the long-term implications of both sides of that coin. It concludes with information on natural ways to lower LDL that work specifically for people with the PCSK9 variants that increase cholesterol levels.

What does the PCSK9 gene do?

The PCSK9 gene codes for an enzyme that is involved in cholesterol transport. The enzyme binds to LDL particles, which transport fat molecules, including cholesterol, throughout the body.

PCSK9 plays a regulatory role in keeping cholesterol at the right level. It controls the number of LDL receptors on liver cells. The liver handles cholesterol regulation for the body – both by synthesis and through elimination.

If you don’t have enough LDL receptors taking up cholesterol, you will have an increase in cholesterol in the bloodstream.

On the other hand, if you have more LDL receptors, your cholesterol levels in the blood will be lower.

Thus, it was quite a breakthrough when researchers figured out that blocking PCSK9 causes an increase in LDL receptors in the liver  — which causes a decrease in overall cholesterol levels.

PCSK9 genetic variants and high cholesterol:

Cholesterol levels in the bloodstream are partly due to diet, however, the bigger player in cholesterol levels is genetics.

Some variants in the PCSK9 gene have links to more PCSK9 protein (gain-of-function) and higher cholesterol levels. A few of the mutations can lead to really high LDL levels known as familial hypercholesterolemia.  Other variants just increase LDL levels a little, so that they are somewhat higher than normal.[ref]

PCSK9 variants and low cholesterol:

After researchers discovered the link between PCSK9 mutations and high cholesterol in 2003, other research showed that there are PCSK9 variants (loss-of-function) that lead to lower cholesterol levels. Variants with the decreased function will cause more LDL receptors in the liver, thus causing more LDL particles (including cholesterol) to be removed from the bloodstream.

Therefore, loss-of-function variants are linked with lower lifetime LDL cholesterol levels and a lower risk of heart disease.[ref][ref] These variants are also associated with a decreased risk of mortality from sepsis.[ref]

PCSK9 and heart disease:

The PCSK9 gain-of-function variants that increase LDL also have links to an increased risk of heart disease and stroke.

A recent meta-analysis that included over 5,000 people found that people with two copies of a PCSK9 variant that increases LDL had a more than 2-fold increased odds of having coronary artery disease.[ref]

Another study that followed participants for 18 years found that a PCSK9 variant is associated with increased arterial plaque. Higher PCSK9 levels were associated with a 2-fold risk of having arterial plaques.[ref]


Genetic variants:

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PCSK9 variants associated with decreased LDL-cholesterol and decreased PCSK9 enzyme function:

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[ref][ref]
  • T/T: decreased LDL-cholesterol, > 30% lower risk of heart disease

Members: Your genotype for rs11591147 is .

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

  • A/A: decreased LDL-cholesterol, lower risk of heart disease[ref][ref], decreased fasting glucose levels[ref]
  • A/C: decreased LDL-cholesterol, lower risk of heart disease, decreased fasting glucose levels
  • C/C: typical

Members: Your genotype for rs28362286 is .

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

  • G/G: decreased LDL and decreased risk of heart disease[ref]
  • C/G: decreased LDL and decreased risk of heart disease
  • C/C: typical

Members: Your genotype for rs67608943 is .

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

  • T/T: decreased LDL and decreased risk of heart disease [ref]
  • C/T: decreased LDL and decreased risk of heart disease
  • C/C: typical

Members: Your genotype for rs72646508 is .


PCSK9 variants associated with increased LDL-cholesterol:

Check your genetic data for rs505151 E670G (23andMe v4, v5; AncestryDNA):

  • G/G: increased LDL, 2-fold increased risk of coronary artery disease[ref][ref][ref][ref]
  • A/G: increased LDL, increased risk of coronary artery disease
  • A/A: typical

Members: Your genotype for rs505151 is .

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

  • C/T: greatly increased LDL, considered pathogenic for familial hypercholesterolemia[ref]
  • T/T: typical

Members: Your genotype for rs28942112 (i5000370) is .

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

  • A/T: greatly increased LDL, considered pathogenic for familial hypercholesterolemia[ref]
  • T/T: typical

Members: Your genotype for rs28942111 is .

 


Lifehacks for lowering LDL:

Natural supplements for LDL and PCSK9:

If you have the genetic variants that increase LDL due to PCSK9: Consider berberine!

Berberine is a natural inhibitor of PCSK9 and has been shown in human studies[ref][ref] and cell studies[ref] to decrease cholesterol.

You can buy berberine as a supplement online or at local stores. Keep in mind if you are a diabetic that berberine can lower blood glucose levels.

Related article: Berberine: Research, absorption, genetic interactions

Quercetin is another flavonoid that may decrease PCSK9. Animal studies show that it moderates LDL levels by decreasing PCSK9.[ref]

Quercetin-rich foods include apples and onions, but it is also found in low amounts in a lot of different fruits and vegetables. (Perhaps this is why eating onions decreases the risk of death from cardiovascular causes.[ref]) In addition, you can also get quercetin as a supplement. Taking it with fat may lead to better absorption.

Related article: Quercetin: Scientific studies plus genetic connections 

PCSK9 inhibitor medications: 

The FDA has approved PCSK9 prescription inhibitors to lower cholesterol levels. If you carry one of the variants above that can lead to familial hypercholesterolemia, you should seriously consider discussing it with your doctor and/or get a full cholesterol panel run.


Related Genes and Topics:

Diet and Blood Pressure: ACE Gene Variants and Saturated Fat
Research shows that people with the ACE deletion genotype are likely to have an increase in blood pressure on a high-fat diet. Find out how a high-fat diet interacts with your genes.

Triglycerides- Genetic variants that impact your 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.

CYP2D6: Variants that cause reactions to common medications
CYP2D6 is responsible for the break down and elimination of about 25% of prescription medications. Genetic variants in CYP2D6 can significantly impact the way that you react to certain drugs.

 

References:

Adorni, Maria Pia, et al. “Effect of a Novel Nutraceutical Combination on Serum Lipoprotein Functional Profile and Circulating PCSK9.” Therapeutics and Clinical Risk Management, vol. 13, 2017, pp. 1555–62. PubMed, https://doi.org/10.2147/TCRM.S144121.
Benn, Marianne, et al. “PCSK9R46L, Low-Density Lipoprotein Cholesterol Levels, and Risk of Ischemic Heart Disease: 3 Independent Studies and Meta-Analyses.” Journal of the American College of Cardiology, vol. 55, no. 25, June 2010, pp. 2833–42. ScienceDirect, https://doi.org/10.1016/j.jacc.2010.02.044.
—. “PCSK9R46L, Low-Density Lipoprotein Cholesterol Levels, and Risk of Ischemic Heart Disease: 3 Independent Studies and Meta-Analyses.” Journal of the American College of Cardiology, vol. 55, no. 25, June 2010, pp. 2833–42. ScienceDirect, https://doi.org/10.1016/j.jacc.2010.02.044.
Blekkenhorst, Lauren C., et al. “Cruciferous and Allium Vegetable Intakes Are Inversely Associated With 15‐Year Atherosclerotic Vascular Disease Deaths in Older Adult Women.” Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, vol. 6, no. 10, Oct. 2017, p. e006558. PubMed Central, https://doi.org/10.1161/JAHA.117.006558.
Cao, Shijie, et al. “Berberrubine and Its Analog, Hydroxypropyl-Berberrubine, Regulate LDLR and PCSK9 Expression via the ERK Signal Pathway to Exert Cholesterol-Lowering Effects in Human Hepatoma HepG2 Cells.” Journal of Cellular Biochemistry, Oct. 2018. PubMed, https://doi.org/10.1002/jcb.27102.
Chen, Suet N., et al. “A Common PCSK9 Haplotype, Encompassing the E670G Coding Single Nucleotide Polymorphism, Is a Novel Genetic Marker for Plasma Low-Density Lipoprotein Cholesterol Levels and Severity of Coronary Atherosclerosis.” Journal of the American College of Cardiology, vol. 45, no. 10, May 2005, pp. 1611–19. PubMed, https://doi.org/10.1016/j.jacc.2005.01.051.
Chikowore, Tinashe, et al. “C679X Loss-of-Function PCSK9 Variant Lowers Fasting Glucose Levels in a Black South African Population: A Longitudinal Study.” Diabetes Research and Clinical Practice, vol. 144, Oct. 2018, pp. 279–85. PubMed, https://doi.org/10.1016/j.diabres.2018.09.012.
Cohen, Jonathan, et al. “Low LDL Cholesterol in Individuals of African Descent Resulting from Frequent Nonsense Mutations in PCSK9.” Nature Genetics, vol. 37, no. 2, Feb. 2005, pp. 161–65. PubMed, https://doi.org/10.1038/ng1509.
—. “Low LDL Cholesterol in Individuals of African Descent Resulting from Frequent Nonsense Mutations in PCSK9.” Nature Genetics, vol. 37, no. 2, Feb. 2005, pp. 161–65. PubMed, https://doi.org/10.1038/ng1509.
—. “Low LDL Cholesterol in Individuals of African Descent Resulting from Frequent Nonsense Mutations in PCSK9.” Nature Genetics, vol. 37, no. 2, Feb. 2005, pp. 161–65. PubMed, https://doi.org/10.1038/ng1509.
Dong, Bin, et al. “Inhibition of PCSK9 Transcription by Berberine Involves Down-Regulation of Hepatic HNF1α Protein Expression through the Ubiquitin-Proteasome Degradation Pathway *.” Journal of Biological Chemistry, vol. 290, no. 7, Feb. 2015, pp. 4047–58. www.jbc.org, https://doi.org/10.1074/jbc.M114.597229.
Ferreira, João Pedro, et al. “PCSK9 Protein and Rs562556 Polymorphism Are Associated With Arterial Plaques in Healthy Middle‐Aged Population: The STANISLAS Cohort.” Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, vol. 9, no. 7, Mar. 2020, p. e014758. PubMed Central, https://doi.org/10.1161/JAHA.119.014758.
Genga, Kelly Roveran, et al. “Impact of PCSK9 Loss-of-Function Genotype on 1-Year Mortality and Recurrent Infection in Sepsis Survivors.” EBioMedicine, vol. 38, Nov. 2018, pp. 257–64. PubMed Central, https://doi.org/10.1016/j.ebiom.2018.11.032.
Kent, Shia T., et al. “PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites.” Circulation. Cardiovascular Genetics, vol. 10, no. 4, Aug. 2017, p. e001632. PubMed, https://doi.org/10.1161/CIRCGENETICS.116.001632.
—. “PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites.” Circulation. Cardiovascular Genetics, vol. 10, no. 4, Aug. 2017, p. e001632. PubMed, https://doi.org/10.1161/CIRCGENETICS.116.001632.
Kwon, H. J., et al. “Molecular Basis for LDL Receptor Recognition by PCSK9.” Proceedings of the National Academy of Sciences, vol. 105, no. 6, Feb. 2008, pp. 1820–25. DOI.org (Crossref), https://doi.org/10.1073/pnas.0712064105.
—. “Molecular Basis for LDL Receptor Recognition by PCSK9.” Proceedings of the National Academy of Sciences, vol. 105, no. 6, Feb. 2008, pp. 1820–25. DOI.org (Crossref), https://doi.org/10.1073/pnas.0712064105.
Li, Yan-yan, et al. “PCSK9 Gene E670G Polymorphism and Coronary Artery Disease: An Updated Meta-Analysis of 5,484 Subjects.” Frontiers in Cardiovascular Medicine, vol. 7, Nov. 2020, p. 582865. PubMed Central, https://doi.org/10.3389/fcvm.2020.582865.
—. “PCSK9 Gene E670G Polymorphism and Coronary Artery Disease: An Updated Meta-Analysis of 5,484 Subjects.” Frontiers in Cardiovascular Medicine, vol. 7, Nov. 2020, p. 582865. PubMed Central, https://doi.org/10.3389/fcvm.2020.582865.
Mbikay, Majambu, et al. “Mice Fed a High-Cholesterol Diet Supplemented with Quercetin-3-Glucoside Show Attenuated Hyperlipidemia and Hyperinsulinemia Associated with Differential Regulation of PCSK9 and LDLR in Their Liver and Pancreas.” Molecular Nutrition & Food Research, vol. 62, no. 9, May 2018, p. e1700729. PubMed, https://doi.org/10.1002/mnfr.201700729.
Postmus, Iris, et al. “PCSK9 SNP Rs11591147 Is Associated with Low Cholesterol Levels but Not with Cognitive Performance or Noncardiovascular Clinical Events in an Elderly Population.” Journal of Lipid Research, vol. 54, no. 2, Feb. 2013, pp. 561–66. PubMed Central, https://doi.org/10.1194/jlr.M033969.
Qiu, Chengfeng, et al. “What Is the Impact of PCSK9 Rs505151 and Rs11591147 Polymorphisms on Serum Lipids Level and Cardiovascular Risk: A Meta-Analysis.” Lipids in Health and Disease, vol. 16, no. 1, June 2017, p. 111. PubMed, https://doi.org/10.1186/s12944-017-0506-6.
—. “What Is the Impact of PCSK9 Rs505151 and Rs11591147 Polymorphisms on Serum Lipids Level and Cardiovascular Risk: A Meta-Analysis.” Lipids in Health and Disease, vol. 16, no. 1, June 2017, p. 111. PubMed, https://doi.org/10.1186/s12944-017-0506-6.
Shapiro, Michael D., et al. “PCSK9: From Basic Science Discoveries to Clinical Trials.” Circulation Research, vol. 122, no. 10, May 2018, pp. 1420–38. PubMed Central, https://doi.org/10.1161/CIRCRESAHA.118.311227.
Slimani, Afef, et al. “Effect of E670G Polymorphism in PCSK9 Gene on the Risk and Severity of Coronary Heart Disease and Ischemic Stroke in a Tunisian Cohort.” Journal of Molecular Neuroscience: MN, vol. 53, no. 2, June 2014, pp. 150–57. PubMed, https://doi.org/10.1007/s12031-014-0238-2.




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.