Abstract 4369082: Population Screening for Polygenic Risk Identifies and Prevents More Cases of Coronary Artery Disease Than Screening for FH

Background: Due to the availability of effective lipid-lowering therapies, familial hypercholesterolemia (FH) case finding is adopted by many healthcare systems. In parallel, polygenic risk scores (PRS) have emerged as a powerful tool for capturing the effect of common genetic variants associated with CAD. Research Question: What proportion of individuals at high PRS for CAD exhibit equivalent risk compared to FH variant carriers, and what are the potential clinical benefits of treating these individuals with statins. Methods: We analyzed data from the UK Biobank, identifying FH carriers via whole-exome sequencing and defining polygenic risk using a CAD PRS. Incident CAD events in statin-naive individuals were compared between FH carriers and individuals with high PRS. Number-needed-to-treat (NNT) with statins and number needed to screen (NNS) were calculated to assess therapeutic impact in high PRS individuals. Results: The top 8% of the PRS distribution exhibited comparable or higher CAD risk than FH carriers. This high-PRS group accounted for between 18 and 29 times more CAD events than FH carriers, depending on age. In the untreated high PRS group the rate of CAD events was 10.28 per 1000 person years (9.01 - 11.67) compared to 6.78 per 1000 person years (5.39 - 8.42) in the treated high PRS group, representing a relative risk reduction (RRR) of 0.34 (0.15 - 0.49). In the median PRS group, the rate of CAD events was 5.28 per 1000 persons (4.67 - 5.94) compared to 3.93 per 1000 person years (3.21 - 4.75) in the treated group, representing a RRR of 0.26 (0.07 - 0.41). The NNT in the high PRS group was 286 compared to 741 in the median PRS group, indicating that statins were roughly 2.6 fold more effective, after matching on clinical risk factors. The NNT (286) for statins in the high PRS group is similar to literature based estimates for statin treatment in FH (222) but the number needed to screen is approximately 21 fold higher for FH than for high PRS. Conclusion: In the population, screening for high CAD PRS individuals will prevent more CAD cases than screening for FH. This is because high PRS individuals are much more prevalent than FH individuals and have enhanced therapeutic benefit from statin treatment (compared to those without high PRS). The polygenic component of CAD is a major, treatable risk factor that is not routinely evaluated in prevention programs, despite a growing body of evidence that this can be implemented easily into clinical practice.