Abstract 4364163: Polygenic Risk Score for Abdominal Aortic Aneurysm in Patients with Cardiometabolic Disease: Analysis of 40,000 Patients from 3 TIMI Trials

Background: Abdominal aortic aneurysm (AAA) is a common and potentially fatal condition when rupture occurs. Current US guidelines recommend screening by ultrasound in men aged 65–75 with a smoking history. However, AAA remains underdiagnosed using these limited clinical criteria, underscoring the need to explore additional risk factors. We evaluated whether the addition of a polygenic risk score (PRS) for AAA helps identify individuals at higher risk among patients with established cardiometabolic disease. Methods: A genetic analysis was performed by pooling individual patient-level data from 3 TIMI trials (FOURIER, ENGAGE-AF and PEGASUS). AAA events were reported by investigators as adverse events, and blinded study physicians independently reviewed and confirmed all cases. We utilized a recently validated AAA PRS (Nat Genet, 2023) and assessed its association with AAA using Cox proportional hazard models adjusted for age, sex, smoking, history of ASCVD, HTN, hyperlipidemia, DM, trial and ancestry (PC1–5). PRS was analyzed continuously (per 1-SD) and categorically (high [top 20%], intermediate [middle 60%], low [bottom 20%]). Results: A total of 39,960 patients were included (median f/u 2.6 years). Individuals in higher PRS categories had a higher rate of AAA events over time ( Figure 1A ). Even after adjusting for clinical risk factors, a 1-SD higher PRS was independently associated with a 54% higher risk of AAA (HR-adj 1.54 [95% CI 1.35–1.76], p<0.001). Compared with low PRS, an intermediate PRS was associated with a 2-fold risk (HR-adj 2.03 [1.23–3.34], p<0.001), and a high PRS with a 3-fold risk (HR-adj 3.12 [1.82–5.36], p<0.001). The magnitude of risk conferred by a high PRS was comparable to traditional clinical risk factors ( Figure 1B ). Coclusion: In patients with cardiometabolic disease, an AAA PRS was independently associated with risk of AAA events, with a magnitude of risk on par with traditional clinical risk factors.