Study Integrating GWAS and pQTL Data Identifies Potential Therapeutic Targets for Hypertension

Area of Science:

• Genetics
• Cardiovascular Medicine
• Pharmacology

Background:

• Hypertension is a leading cause of cardiovascular disease, often poorly managed despite existing therapies.
• Identifying novel, genetically supported drug targets is crucial for improving hypertension treatment outcomes.

Purpose of the Study:

• To identify plasma proteins causally associated with hypertension using proteome-wide Mendelian Randomization (MR).
• To evaluate the therapeutic potential of identified protein targets for novel hypertension drug development.

Main Methods:

• Two-sample MR analysis of plasma protein quantitative trait loci (pQTLs) and hypertension Genome-Wide Association Study (GWAS) data.
• Colocalization, enrichment analysis, and Protein-Protein Interaction (PPI) analysis were employed.
• Drug prediction and molecular docking assessed the therapeutic potential of candidate targets.

Main Results:

• MR analysis identified 12 plasma proteins associated with hypertension; three (ACE, AGT, NPPA) were supported by colocalization.
• ACE and AGT are known targets, while NPPA represents a novel, underexplored target.
• Drug prediction and molecular docking revealed stable interactions and strong binding affinities for candidate drugs.

Conclusions:

• Genetically determined levels of ACE, AGT, and NPPA show a causal link to hypertension.
• NPPA is highlighted as a novel, genetically supported protective target alongside established renin-angiotensin system components.
• These proteins offer promising avenues for developing innovative hypertension therapeutics.