Polygenic Risk Scores for Cardiovascular Risk Stratification and Lipid Therapy

Polygenic risk scores (PRS) have emerged as promising tools for personalized atherosclerotic cardiovascular disease (ASCVD) prevention. However, conventional risk prediction models frequently fail to identify high-risk individuals before clinical disease develops, resulting in suboptimal preventive strategies. The comparative effectiveness of different PRS models and their ability to guide intensity of lipid-lowering therapy remain uncertain.A systematic search of PubMed, Embase, Scopus, and the Cochrane Library was conducted from inception through June 2026 to identify studies evaluating polygenic risk scores (PRS) for ASCVD prevention. Network meta-analysis was performed using the R meta package. Risk of bias was assessed using RoB 2.0. Discrimination, reclassification, and treatment-effect modification were evaluated.A total of 6 studies involving 577,289 participants were included, comprising 318,600 (55.2%) men and 258,689 (44.8%) women. Mean age ranged from 45-68 years, with baseline LDL-C levels between 92-194 mg/dL. Study quality was high, with an overall low risk of bias. PRS-guided risk assessment significantly improved cardiovascular risk stratification compared with conventional clinical models. Net reclassification improvement ranged from 3.4% (95% CI 1.5-5.3) to 24.0% (95% CI 18.5-29.5), with the greatest benefit observed among younger individuals and those at intermediate baseline risk. Multi-ethnic PRS models demonstrated consistent performance across diverse populations, achieving reclassification improvements of 6.0% (95% CI 4.5-7.5), while genome-wide CAD-PRS models yielded improvements of 4.0% (95% CI 2.8-5.2). High genetic-risk individuals derived substantially greater benefit from intensive lipid-lowering therapy, with significant reductions in major adverse cardiovascular events (HR 0.47; 95% CI 0.38-0.58). Treatment effects were most pronounced in high-PRS groups (HR 0.41; 95% CI 0.31-0.53) compared with low-PRS groups (HR 0.67; 95% CI 0.47-0.97). No increase in adverse events was observed (RR 1.02; 95% CI 0.96-1.08).Polygenic risk scores significantly enhance ASCVD risk stratification beyond conventional clinical models and identify individuals most likely to benefit from intensive lipid-lowering therapy. PRS-guided prevention improves risk reclassification, enables more personalized treatment allocation, and may optimize preventive cardiovascular care without compromising safety across diverse populations.