Derivation and Validation of Genome-Wide Polygenic Score for Ischemic Heart Failure

Area of Science:

• Genetics
• Cardiology
• Precision Medicine

Background:

• Mortality from ischemic heart failure (HF) in patients with coronary artery disease (CAD) remains high despite advances in management.
• Genetics plays a partial role in HF, and reliable risk stratification tools are lacking.
• Developing a polygenic risk score (PRS) for HF in CAD patients is crucial for improved risk assessment.

Purpose of the Study:

• To develop and validate a polygenic risk score (HF-PRS) for predicting HF in patients with CAD.
• To assess the association of HF-PRS with ischemic HF, independent of obstructive CAD.
• To evaluate the performance of HF-PRS in a high-risk subgroup of CAD patients.

Main Methods:

• Utilized summary statistics from a genome-wide association study for HF.
• Developed candidate PRSs using pruning and thresholding and LDPred in the Mount Sinai BioMe CAD cohort (N=6274).
• Validated the best-performing score in the Penn Medicine BioBank cohort (N=7250) and performed subgroup analysis.

Main Results:

• HF-PRS showed a significant association with ischemic HF in European ancestry patients with CAD in both cohorts (OR 1.14 and 1.07 per SD).
• The association remained significant after adjusting for obstructive CAD.
• In a high-risk subgroup, individuals in the top 10th percentile of HF-PRS had double the odds of ischemic HF compared to the bottom 10th percentile.

Conclusions:

• A polygenic risk score for HF (HF-PRS) can effectively stratify risk in patients with coronary artery disease.
• HF-PRS demonstrates potential as a tool for identifying individuals at elevated risk of ischemic HF.
• Further prospective studies are warranted to confirm clinical utility for patient care.