​Comprehensive mendelian randomization analysis of plasma proteomics to identify new therapeutic targets for the...

Area of Science:

• Cardiovascular Genetics
• Proteomics
• Systems Biology

Background:

• Ischemic heart disease is a leading global cause of mortality.
• Effective therapeutic strategies for coronary heart disease (CHD) and myocardial infarction (MI) require further development.
• Identifying causal links between plasma proteins and these conditions is crucial for therapeutic advancement.

Purpose of the Study:

• To identify potential therapeutic targets for CHD and MI.
• To investigate the causal relationships between plasma proteins and CHD/MI.
• To explore the roles of specific proteins in the pathogenesis of these cardiovascular diseases.

Main Methods:

• A two-sample Mendelian randomization (MR) study analyzed over 1600 plasma proteins for causal associations with CHD and MI.
• MR findings were validated using Bayesian colocalization, SMR, and TWAS analyses.
• Further investigations included enrichment analysis, single-cell analysis, MR of cardiovascular risk factors, Phe-MR, and protein-protein interaction network construction.

Main Results:

• Thirteen proteins showed causal associations with CHD, and seven were also causal for MI.
• FES protein was found to be protective against both CHD and MI (e.g., OR=0.65 for MI).
• PCSK9 protein was identified as a risk factor for both CHD and MI (e.g., OR=1.36 for MI).

Conclusions:

• FES and PCSK9 proteins have significant causal roles in CHD and MI.
• FES demonstrates a protective effect, while PCSK9 acts as a risk factor.
• These proteins represent promising therapeutic targets for the development of novel drugs to treat CHD and MI.