Polygenic Risk Scores for Cardiovascular Disease Predict Risk Factor Control and Residual Cardiovascular Risk in Stroke Survivors

Background: Stroke remains a leading cause of mortality and long-term disability worldwide, with high residual vascular risk among survivors despite optimal secondary prevention. The contribution of inherited polygenic risk to this residual vulnerability remains unclear. Methods: We analyzed 2,701 stroke survivors (mean age 59.8{+/-}7.1 years, 61.7% male) from the UK Biobank. Stroke- and coronary artery disease (CAD)-polygenic risk scores (metaGRS), comprising approximately 3.2 million and 1.7 million genetic variants, respectively, were derived from large-scale genome-wide association studies using penalized regression. The primary outcome was major adverse cardiovascular events (MACE), while secondary outcomes included recurrent stroke and vascular risk factor control. metaGRS associations with incident MACE and recurrent stroke were tested using Cox models, whereas associations with baseline risk-factor control were assessed using logistic regression. Mediation analyses quantified indirect effects of metaGRS to MACE via HbA1c, LDL cholesterol, and blood pressure. Results: Over 12 years, 731 MACE events (27.1%) and 351 recurrent stroke events (13.0%) occurred. CAD-metaGRS was independently associated with future MACE (age- and sex-adjusted HR per SD increment 1.15, 95%CI 1.07-1.24; p<0.001), whereas higher stroke- and CAD metaGRS were both associated with poorer glycemic control. A higher CAD-metaGRS was also associated with poorer lipid control. Mediation analyses identified glycemic regulation as a significant pathway linking polygenic risk to recurrent vascular events. Conclusions: Polygenic risk scores for cardiovascular disease are associated with recurrent vascular events and vascular risk factor control among stroke survivors, pointing to potentially actionable insights in secondary prevention that merit further investigation.