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

LDL particles bind to LDL receptors which allows the liver (or other cell membranes) to use the fats within the cells. Too few LDL receptors can cause cholesterol levels to increase.  PCSK9 plays a regulatory role in keeping cholesterol at the right level.

Either blocking PCSK9 with medications or carrying a PCSK9 mutation that decreases its function will cause more LDL receptors on the cell surface, thus causing more LDL particles (including cholesterol) to be removed from the bloodstream.

On the other hand, too much of the PCSK9 enzyme can cause higher cholesterol levels. One genetic cause of familial hypercholesterolemia (genetically caused high cholesterol) is mutations of the PCSK9 gene.


PCSK9 Variants associated with decreased LDL-cholesterol(less PCSK9 enzyme function):

Check your 23andMe data for rs11591147 R46L (v4, v5):

  • GG: normal
  • GT: decreased LDL-cholesterol, 30% lower risk of heart disease[ref] [ref]
  • TT: decreased LDL-cholesterol, > 30% lower risk of heart disease

Check your 23andMe data for rs28362286 C679X (v4 only):

  • AA: decreased LDL-cholesterol, lower risk of heart disease [ref][ref], decreased fasting glucose levels [ref]
  • AC: decreased LDL-cholesterol, lower risk of heart disease, decreased fasting glucose levels
  • CC: normal

Check your 23andMe data for rs67608943 Y142X (v4, v5):

  • GG: decreased LDL and decreased risk of heart disease [ref]
  • CG: decreased LDL and decreased risk of heart disease
  • CC: normal

Check your 23andMe data for rs72646508 L253F (v4, v5):

  • TT: decreased LDL and decreased risk of heart disease  [ref]
  • CT: decreased LDL and decreased risk of heart disease
  • CC: normal

PCSK9 variants associated with increased LDL-cholesterol:

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

  • GG: increased LDL, increased risk of coronary artery disease[ref] [ref] [ref]
  • AG: increased LDL, increased risk of coronary artery disease
  • AA: normal

Check your 23andMe data for i5000370 -rs28942112 (v4 only):

  • CT: greatly increased LDL, considered pathogenic for familial hypercholesterolemia[ref]
  • TT: normal

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

  • AT: greatly increased LDL, considered pathogenic for familial hypercholesterolemia[ref]
  • TT: normal

 


Lifehacks:

There are PCSK9 inhibitors that are FDA approved prescription medications for lowering 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.

Berberine is a natural inhibitor of PCSK9 and has been shown in human studies[ref][ref] and cell studies[ref] to decrease cholesterol. (Note – this isn’t going to inhibit PCSK9 as much as the prescription medications.) You can buy berberine as a supplement on Amazon or at local stores. Keep in mind that it is also known to lower blood glucose levels, which could interfere with medications if you are diabetic.

Other articles you may enjoy:

Low HDL Cholesterol Levels Can Be Genetic

Mediterranean Diet and Your Genes

Lipoprotein(a): A big genetic risk for heart disease

 


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