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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, transporting 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 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 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 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]


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Lifehacks for lowering LDL:

Natural supplements for LDL and PCSK9:

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering from Colorado School of Mines and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.