Mendelian randomization studies on atherosclerotic cardiovascular disease: evidence and limitations

Area of Science:

• Cardiovascular Epidemiology
• Genetic Epidemiology
• Biomarker Discovery

Background:

• Epidemiological studies identify numerous biomarkers linked to atherosclerotic cardiovascular diseases (ASCVD) risk.
• The causal role of these biomarkers in ASCVD etiology is often unclear.
• Mendelian randomization (MR) is a genetic approach to distinguish causal risk factors from disease indicators.

Purpose of the Study:

• To review high-quality MR studies investigating the causal relationship between biomarkers and ASCVD.
• To evaluate the utility of MR in validating biomarkers as potential therapeutic targets for ASCVD.
• To compare MR findings with results from randomized clinical trials (RCTs) for ASCVD treatments.

Main Methods:

• Systematic selection of high-quality MR studies focused on ASCVD.
• Analysis of causal associations between various biomarkers and ASCVD.
• Comparative analysis of MR results against established RCT outcomes for ASCVD therapies.

Main Results:

• MR studies have successfully clarified the causal roles of numerous biomarkers in ASCVD.
• A strong agreement was observed between MR-derived causal inferences and RCT findings.
• MR shows promise as an efficient screening tool for identifying novel therapeutic targets in ASCVD drug development.

Conclusions:

• Mendelian randomization is a valuable tool for establishing causality in ASCVD biomarker research.
• The concordance between MR and RCTs supports MR's role in preclinical drug target validation.
• Careful consideration of MR assumptions and limitations, alongside methodological advancements, is crucial for robust study design and interpretation.