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

Familial Hypercholesterolemia (FH): Premature Cardiovascular Risk Reduction Through Early Action. 3 Genes Affecting LDL Clearance Can Cause FH 1000+ Mutations Identified to Date.

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

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

  2. 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 LDL particle Circulation Liver cell 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 Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.

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

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

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

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

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