Polygenic Risk Score Informed Clinical Model for Improving Abdominal Aortic Aneurysm Screening

Area of Science:

• Cardiovascular Genetics
• Epidemiology
• Medical Diagnostics

Background:

• Abdominal aortic aneurysm (AAA) is a complex disease influenced by environmental and genetic factors.
• Polygenic risk scores (PRSs) effectively stratify cardiovascular disease risk using single nucleotide variants (SNVs).
• Assessing PRS for AAA (PRS_AAA) can improve individual risk stratification and screening strategies.

Purpose of the Study:

• To evaluate the association of PRS_AAA with incident AAA risk.
• To analyze the effectiveness of a combined clinical-genetic risk model (Prob-AAA) for AAA.
• To explore the clinical utility of Prob-AAA in identifying individuals for AAA screening.

Main Methods:

• Calculated PRS_AAA using 911,440 SNVs and PRS for coronary artery disease using 2,324,683 SNVs from mixed-ancestry GWAS.
• Utilized the UK Biobank prospective cohort, including individuals with complete genetic data and no prior AAA diagnosis.
• Developed the Prob-AAA model incorporating clinically significant variables and PRS_AAA.

Main Results:

• The study included 481,105 individuals with 2,668 incident AAA cases.
• Incident AAA risk increased significantly across PRS_AAA deciles (0.30% to 0.93%).
• The Prob-AAA model independently predicted incident AAA (HR 1.92) and identified more cases (9.6%) than PRS_AAA alone (4.2%) or current screening guidelines (capturing 5.7% of the cohort with a 3.2% incident AAA rate).

Conclusions:

• The PRS-informed Prob-AAA model significantly enhances predictive power for AAA compared to existing clinical risk factor-based guidelines.
• Prob-AAA demonstrates clinical utility by identifying additional high-risk individuals, particularly males not covered by current screening protocols.
• This genetic-clinical model offers a more precise approach to AAA screening and risk stratification.