Endothelial cell-related genetic variants identify LDL cholesterol-sensitive individuals who derive greater benefit from aggressive lipid lowering.

Summary

Using genome-wide CAD variants with endothelial functional effects, the authors built a 35-SNP EC-specific polygenic risk score that was associated with incident CAD in UK Biobank and identified individuals who derive greater benefit from aggressive LDL-C lowering in JUPITER (statin) and FOURIER (PCSK9 inhibitor). This enables endothelial biology–informed precision prevention.

Key Findings

• A 35-variant endothelial cell–specific PRS (EC PRS) was constructed from CAD-associated SNPs.
• EC PRS independently associated with incident CAD in UK Biobank (n=348,967; aHR per 1 SD ~1.24).
• In JUPITER (n=8,749) and FOURIER (n=14,298), EC PRS identified individuals deriving greater benefit from aggressive LDL-C lowering.

Clinical Implications

Clinicians could prioritize high-intensity statins or PCSK9 inhibitors for patients with high EC PRS, potentially maximizing absolute risk reduction while improving cost-effectiveness in primary and secondary prevention.

Limitations

• Ancestry composition and potential reduced generalizability to non-European populations are not fully detailed.
• Therapy-response inference is based on stratified analyses of existing trials, not a prospectively PRS-stratified randomized trial.

Future Directions

Prospective PRS-guided randomized trials to test clinical utility; evaluation across ancestries; integration with clinical risk calculators for treatment allocation.