PCSK9

HIGH

Proprotein convertase subtilisin/kexin type 9

Chromosome: 1p32.3

Gene Overview

PCSK9 encodes proprotein convertase subtilisin/kexin type 9, a serine protease that binds the LDL receptor and targets it for lysosomal degradation. By reducing hepatic LDLR abundance, PCSK9 raises plasma LDL cholesterol levels. Gain-of-function mutations cause autosomal dominant hypercholesterolemia, while loss-of-function variants confer lower LDL-C and reduced coronary artery disease risk. PCSK9 inhibitors (evolocumab, alirocumab) have emerged as potent LDL-lowering therapies. The gene is expressed primarily in liver, intestine, and kidney. GWAS consistently implicate PCSK9 in LDL-C and CAD susceptibility.

Molecular Function

  • proteolytic activity
  • LDLR binding
  • receptor degradation
  • cholesterol regulation

Protein class: proprotein convertase

Regulatory Annotation

Promoter activity: SREBP-2 regulates PCSK9 transcription; sterol depletion increases expression.

Enhancer associations: CAD-associated variants influence PCSK9 expression in hepatocytes.

eQTL tissues: liver

Tissue Expression Context

liverTPM range: 25-80GTEx vv8
small intestineTPM range: 5-20GTEx vv8

Pathways

Linked Diseases & Exposures

Diseases

Exposures

Mechanistic Hypotheses

PCSK9-mediated LDLR degradation limits hepatic cholesterol clearance; elevated PCSK9 increases LDL-C and atherosclerosis risk; inhibition restores LDLR and reduces cardiovascular events.

Clinical trials show PCSK9 inhibitors lower LDL-C and CAD events; loss-of-function carriers have reduced MI risk.

HIGH

Confidence Rating

Overall evidence confidence for this gene entry: HIGH

References

  1. 1.Abifadel M, et al. (2003). Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature Genetics. doi:10.1038/ng1161
  2. 2.GTEx Consortium (2020). GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. doi:10.1126/science.aaz1776
  3. 3.Sabatine MS, et al. (2017). Evolocumab and clinical outcomes in patients with cardiovascular disease. New England Journal of Medicine. doi:10.1056/NEJMoa1615664