A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis.
Polymorphisms in myocyte enhancer factor 2A, a transcription factor, tumor necrosis factor (ligand) superfamily, member 4, the OX40 ligand, and proprotein convertase subtilisin/kexin type 9, which affect low-density lipoprotein levels, have all been associated with an altered risk of coronary artery disease and myocardial infarction.
Genetic variation in proprotein convertase subtilisin/kexin type 9 (PCSK9) gene has been recently identified as an important determinant of plasma LDL-cholesterol and severity of coronary heart disease.
PCSK9 gain of function mutations cause hypercholesterolaemia by a reduction of LDL receptor levels, while PCSK9 loss of function variants are associated with a reduction of LDL-C values and a decreased risk of coronary heart disease.
We review here the current understanding of PCSK9 and its potential as a therapeutic target through which to reduce LDL cholesterol for prevention and treatment of coronary heart disease.
The PCSK9 gene E670G polymorphism affects low-density lipoprotein cholesterol levels but is not a risk factor for coronary artery disease in ethnic Chinese in Taiwan.
Autosomal dominant hypercholesterolemia (ADH), a major risk for coronary heart disease, is associated with mutations in the genes encoding the low-density lipoproteins receptor (LDLR), its ligand apolipoprotein B (APOB) or PCSK9 (Proprotein Convertase Subtilin Kexin 9).
PCSK9 regulates low density lipoprotein receptor (LDLR) levels and consequently is a target for the prevention of atherosclerosis and coronary heart disease.
Consequently, the role of PCSK9 in modulating circulating LDL makes it a promising therapeutic target for treating hypercholesterolemia and coronary heart disease.
The R46L variant in the proprotein-convertase subtilisin-kexin type 9 (PCSK9) gene was associated with reduced levels of LDL and total cholesterol and with a lower risk of coronary artery disease.
Proprotein convertase subtilisin kexin 9 (PCSK9) is a new actor discovered in 2003 that is implicated in autosomal dominant hypercholesterolemia, cholesterol homeostasis and coronary heart disease.
Since the loss-of-function mutations in humans are associated with protection against coronary heart disease, and with no apparent deleterious effects, PCSK9 inhibition is becoming attractive as a new strategy for lowering LDL cholesterol (LDL-C) levels, particularly in combination with statins.
Familial Hypercholesterolaemia (FH) is an autosomal dominant disease, caused by mutations in LDLR, APOB or PCSK9, which results in high levels of LDL-cholesterol (LDL-C) leading to early coronary heart disease.
Loss-of-function mutations in PCSK9 result in significantly decreased LDL-cholesterol levels and a disproportionately large reduction in coronary heart disease risk by reducing the exposure to LDL-cholesterol throughout life.
Accordingly, PCSK9 could represent a safe and effective pharmacological target to increase clearance of LDL-C and to reduce the risk of coronary heart disease.
Recent evidence indicates that PCSK9 also modulates the metabolism of triglyceride-rich apolipoprotein B (apoB) lipoproteins, another important coronary heart disease risk factor.
Loss-of-function mutations in PCSK9 cause familial hypobetalipoproteinemia, which appears to lower risk for coronary artery disease and has no adverse sequelae.
This review aims to discuss the impact of natural mutations in the PCSK9 gene on cholesterol metabolism and thus coronary artery disease, as well as molecular mechanisms and therapeutic strategies for PCSK9 inhibition.
It is an autosomal dominant disease, caused by variants in Ldlr, ApoB or Pcsk9, which results in high levels of LDL-cholesterol (LDL-C) leading to early coronary heart disease.