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Familial Hypercholesterolemia (FH):

Premature Cardiovascular Risk ReductionThrough Early Action

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3 Genes Affecting LDL Clearance Can Cause FH1000+ 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

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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.

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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.

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PCSK9 Mutations Increase Degradation of LDL Receptors, Limiting Binding and Endocytosis

ApoB

PCSK9

LDL particle

LDL receptor

LDL receptorsdegraded at a faster rate by increased PCSK9 activity

Normal FH: PCSK9+Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.

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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.