Abstract 4142030: A Polygenic Score to Identify Risk of Incident Stroke and Benefit from Primary Prevention Statin Therapy

Background: Primary prevention statin use has been shown to significantly reduce the incidence of stroke, however, clinical risk scores for statin eligibility do not predict stroke specifically. A polygenic risk score (PRS) for stroke is a tool that may help identify individuals at greatest risk of stroke and most likely to benefit from statin therapy. Methods: We performed a prospective cohort study using genotyped individuals from a large primary prevention RCT (JUPITER), which tested rosuvastatin 20 mg daily vs placebo. We applied the validated GIGASTROKE PRS categorized by quintiles: low (Q1), moderate (Q2-Q4) or high risk (Q5). The primary outcome was occurrence of all-cause stroke. PRS risk was modeled per 1-SD and hazard ratios calculated for the moderate and high-risk groups relative to low risk. Formal testing of treatment interaction for rosuvastatin and PRS was performed. Results: Of 8,749 patients with genetic data (32% male, mean age 66), the median LDL-C was 110 mg/dL and hsCRP was 4.05 mg/L. During 4 years of follow up, 44 patients suffered a stroke. The PRS was strongly associated with risk of incident stroke ( Fig, A ). Compared to those at low genetic risk, the absolute risk of stroke was more than 2-fold greater in the moderate group (HR: 2.10, 0.78-5.67) and nearly 4-fold greater in the high-risk group (HR: 3.72, 1.27-10.88, p-trend =0.011). In this genetic cohort, rosuvastatin reduced the risk of stroke by 61% (HR: 0.39, 0.20-0.76, p=0.006). The relative risk reductions with rosuvastatin were 37% (HR 0.63, 0.11-3.77), 63% (HR 0.37, 0.16-0.88), and 68% (HR 0.32, 0.09-1.17) in low, moderate, and high-risk groups, respectively. The absolute risk reductions with rosuvastatin were 0.13% (-0.38-0.63), 0.46% (0.08-0.84), and 0.76% (-0.03-1.56) ( Fig, B) . Rosuvastatin in the high-risk subgroup reduced the incidence of stroke to the level of the low-risk subgroup receiving placebo (0.35%). Conclusion: A PRS can identify primary prevention patients with a 2 to 4-fold increased risk of stroke, which appears to be largely offset with statin therapy. As the use of PRSs increase in clinical practice, it may be a useful tool to help guide statin initiation for primary stroke prevention.