PCSK9
Proprotein convertase subtilisin/kexin type 9
Gene Number: 255738
Location: 1p32.3
Key Functions: LDL receptor regulation, cholesterol clearance, lipid metabolism, cardiovascular homeostasis, atheroprotection
PCSK9 (proprotein convertase subtilisin/kexin type 9) encodes a secreted serine protease that plays a central role in cholesterol regulation by controlling the number of low-density lipoprotein receptors (LDLR) on the surface of hepatocytes. By modulating LDL receptor availability, PCSK9 determines how effectively the liver can remove LDL cholesterol (LDL-C)—commonly known as “bad cholesterol”—from the circulation.
Under physiological conditions, newly synthesized PCSK9 is secreted by hepatocytes into the plasma, where it binds to the extracellular domain of LDL receptors. Once the PCSK9–LDLR complex is internalized via endocytosis, PCSK9 prevents the normal recycling of the receptor back to the cell surface by targeting it for lysosomal degradation. As a result, fewer LDL receptors remain available on the hepatocyte membrane, leading to reduced LDL uptake and higher plasma cholesterol levels.
Conversely, when PCSK9 activity is reduced—either through genetic variants or pharmacological inhibition—LDL receptors are spared from degradation and recycled more efficiently. This leads to a significant increase in hepatic LDL clearance, markedly lowering circulating LDL-C levels and providing a powerful protective effect against atherosclerosis and cardiovascular disease.
SNP ID | Your Genotype | Alternative Alleles | Interpretation |
|---|---|---|---|
rs11591147 | Analyze your DNA to see your genotype | T | Analyze your DNA to see a personalized result. |
rs11591147
GG – Typical PCSK9 function; standard LDL-C levels and heart disease risk (R).
GT – Loss-of-function allele (T), associated with approximately 2–3× reduced risk of heart disease (R).
TT – Rare homozygous; strong reduction in PCSK9 activity, significantly lower LDL-C and cardiovascular risk. (R; magnitude up to ~4.5× reduction in disease risk) (R).
Functional effect: The T allele disrupts PCSK9's degradation of LDL receptors, resulting in elevated LDL receptor availability, lower LDL-C, and strong protection against cardiovascular disease in multiple studies (R).
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