1. 1 Familial Hypercholesterolemia (FH): Premature Cardiovascular Risk Reduction Through Early Action

2. 2 3 Genes Affecting LDL Clearance Can Cause FH 1000+ Mutations Identified to Date APOB (6 mutations identified) Codes for production of ligand protein, ApoB, which connects LDL particle to receptor Rader DJ, et al. J Clin Invest. 2003;111:1795-1803. LDL particle Liver cell Circulation LDLR (>1000 mutations) codes for LDL receptor which binds to ApoB on LDL particle inducing endocytosis of LDL PCSK9 (8 GOF mutations identified to date) codes for PCSK9 enzyme, which degrades the LDL receptor

3. 3 Normally, LDL Receptors on hepatocytes help to clear LDL Particles from plasma LDL particle Liver cell Circulation Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.

4. 4 LDL Receptor (LDLR) Mutations Alter LDL Receptors, Preventing Attachment to Particle ApoB LDL particle LDL receptor LDL receptor binding site impaired function prevents binding to LDL particle Normal FH: LDLR- Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.

5. 5 PCSK9 Mutations Increase Degradation of LDL Receptors, Limiting Binding and Endocytosis ApoB PCSK9 LDL particle LDL receptor LDL receptors degraded at a faster rate by increased PCSK9 activity Normal FH: PCSK9+ Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.

6. 6 APOB Mutations Alter Shape of Apo B Ligand on LDL, Impeding Ability to “Grab” the LDL Receptor ApoB LDL particle LDL receptor Normal FH: APOB- Mutation impairs ApoB- binding ability to LDL receptor Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.