PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9)

Overview

The PCSK9 gene encodes a protein that plays a central role in cholesterol metabolism. It regulates the number of LDL receptors on liver cells and is thus a major factor in LDL cholesterol levels and cardiovascular risk.

📍 Position
1p32.3 (Chromosome 1)

🏷️ Category
Metabolism

⚡ Function
LDL Receptor Degradation

📊 Frequency
R46L (Protective): ~1-3%

PCSK9 & LDL Cholesterol

The function of PCSK9 is well understood and has led to a new class of cholesterol-lowering drugs:

The PCSK9 Mechanism:

Normal Function: PCSK9 binds to LDL receptors (LDLR) on liver cells
Degradation: It prevents LDLR recycling and directs them to lysosomal destruction
Result: Fewer LDLR on the surface → less LDL cholesterol removed from the blood

High PCSK9 Activity (Risk)

Fewer LDL receptors on the liver
High LDL-C blood levels (~200-400 mg/dL)
Increased risk of heart attack
Gain-of-function mutations

Low PCSK9 Activity (Protection)

More LDL receptors on the liver
Very low LDL-C levels (~50-80 mg/dL)
50-88% risk reduction for heart attack
Loss-of-function mutations (R46L)

💊 PCSK9 Inhibitors: Drugs like Evolocumab (Repatha) and Alirocumab (Praluent) are antibodies that block PCSK9. They lower LDL-C by 50-60% and are used for severe hypercholesterolemia or statin intolerance.

🧬 Genetic Variant

rs562556 (R46L)
1:55505647

Glycine (Normal)

Leucine (Protective)

Arg46Leu (R46L): The T-allele (Leucine) is a loss-of-function variant with significant cardiovascular protection.

Protection via T-Allele:

15-30% lower LDL cholesterol levels
28-50% lower risk of heart attack
No increased risk of side effects
“Natural remedy” effect!

⚠️ On the other hand: Gain-of-Function – There are also rare PCSK9 mutations that increase activity. These lead to autosomal dominant hypercholesterolemia (ADH) and very early risk of heart attack.

💉 PCSK9 Inhibitor Therapy

The discovery of the PCSK9 mechanism revolutionized the treatment of hypercholesterolemia:

Evolocumab (Repatha)

Subcutaneous injection every 2-4 weeks
LDL-C reduction: ~55-60%
In addition to statins or in case of intolerance

Alirocumab (Praluent)

Subcutaneous injection every 2-4 weeks
LDL-C reduction: ~50-58%
FOURIER/ODYSSEY studies: Reduction in cardiovascular events

🔬 New Developments: Inclisiran (Leqvio) is an siRNA-based medication that reduces PCSK9 production in the body. Only 2 injections per year required!

📚 Data Sources

OMIM: #607786 (PCSK9 Gene)
dbSNP: rs562556 (R46L)
PubMed: Cohen et al. (2006) – Sequence variations in PCSK9
NEJM: FOURIER and ODYSSEY trials on PCSK9 inhibitors
Nature: Abifadel et al. (2003) – Discovery of PCSK9

Last Update: February 2026

PCSK9