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.
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.
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 are linked with 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]
Interestingly, PCSK9 gain-of-function variants that increase LDL are also linked to an increased risk of heart disease and stroke.
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 decreased risk of mortality from sepsis.[ref]
PCSK9 variants associated with decreased LDL-cholesterol and decreased PCSK9 enzyme function:
Check your genetic data for rs11591147 R46L(23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs11591147 is —.
Check your genetic data for rs28362286 (23andMe v4; AncestryDNA):
Members: Your genotype for rs28362286 is —.
Check your genetic data for rs67608943 (23andMe v4, v5;):
Members: Your genotype for rs67608943 is —.
Check your genetic data for rs72646508 (23andMe v4, v5):
Members: Your genotype for rs72646508 is —.
PCSK9 variants associated with increased LDL-cholesterol:
Check your genetic data for rs505151 (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs505151 is —.
Check your genetic data for rs28942112 (23andMe i5000370, v4; AncestryDNA):
Members: Your genotype for rs28942112 (i5000370) is .
If you have the genetic variants that increase LDL due to PCSK9: Think about berberine!
You can buy berberine as a supplement online or at local stores. If you are diabetic, keep in mind berberine is known to lower blood glucose levels.
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.
Prescription Meds: 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.
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