Cholesteryl Ester Transfer Protein Deficiency and Hyperalphalipoproteinemia

Area of Science:

• Cardiovascular Science
• Lipid Metabolism
• Ophthalmology

Background:

• Cholesteryl ester transfer protein (CETP) plays a crucial role in lipoprotein metabolism.
• CETP deficiency and CETP inhibitors influence high-density lipoprotein (HDL) cholesterol levels.
• Associations between lipid profiles, atherosclerotic cardiovascular disease (ASCVD), and age-related macular degeneration (ARMD) are under investigation.

Purpose of the Study:

• To compare lipoprotein phenotypes in CETP deficiency versus CETP inhibitor use.
• To summarize and discuss the effects of CETP modulation on ASCVD and ARMD risks.
• To explore the implications of extremely high HDL cholesterol levels.

Main Methods:

• Literature review and summary of existing studies on CETP deficiency and inhibitors.
• Analysis of data regarding ASCVD prevalence in CETP deficiency variants (heterozygotes and homozygotes).
• Discussion of multifactorial hyperalphalipoproteinemia and its association with ARMD.

Main Results:

• CETP deficiency, particularly in heterozygotes with truncated variants, is associated with reduced low-density lipoprotein cholesterol and decreased ASCVD risk.
• ASCVD prevalence was not elevated in individuals with complete CETP deficiency (homozygotes).
• The etiological basis for the association between ASCVD and ARMD in cases of very high HDL cholesterol needs clarification.

Conclusions:

• CETP deficiency confers a degree of protection against ASCVD.
• The link between extremely high HDL cholesterol, ASCVD, and ARMD in multifactorial hyperalphalipoproteinemia warrants further etiological research.
• Challenges in CETP inhibitor development, including recent findings on obicetrapib, are highlighted.