Causal Effect of Lipids and Lipoproteins on Atherosclerosis: Lessons from Genomic Studies

Area of Science:

• Cardiovascular Medicine
• Genetics
• Biochemistry

Background:

• Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of mortality worldwide.
• Lipoproteins, particularly apolipoprotein B (apoB)-containing particles, are implicated in ASCVD pathogenesis.
• The precise role of cholesterol content versus particle retention in ASCVD risk remains debated.

Purpose of the Study:

• To investigate the causal and cumulative effects of apoB-containing lipoproteins on ASCVD risk.
• To determine the factors influencing the clinical benefit of lipid-lowering therapies.
• To clarify the mechanism of atherogenesis, distinguishing between lipoprotein cholesterol content and particle retention.

Main Methods:

• Utilized Mendelian randomization studies to establish causal relationships.
• Analyzed the impact of absolute reduction and duration of exposure to apoB-containing lipoproteins.
• Contrasted lipoprotein retention theory with cholesterol efflux mechanisms.

Main Results:

• Mendelian randomization confirmed causal and cumulative effects of apoB-containing lipoproteins on ASCVD risk.
• Clinical benefit of lipid-lowering therapies is linked to both the magnitude of apoB reduction and treatment duration.
• Evidence suggests lipoprotein retention, not cholesterol content, drives atherosclerosis.

Conclusions:

• ApoB-containing lipoproteins are key causal factors in ASCVD.
• Therapeutic strategies should focus on sustained reduction of apoB-lipoprotein exposure.
• High-density lipoprotein-mediated cholesterol efflux may not be a primary protective mechanism against ASCVD.