A novel polygenic risk score improves prognostic prediction of heart failure with preserved ejection fraction in the Chinese Han population

AIMS: Mortality risk assessment in patients with heart failure (HF) with preserved ejection fraction (HFpEF) presents a major challenge. We sought to construct a polygenic risk score (PRS) to accurately predict the mortality risk of HFpEF. METHODS AND RESULTS: We first carried out a microarray analysis of 50 HFpEF patients who died and 50 matched controls who survived during 1-year follow-up for candidate gene selection. The HF-PRS was developed using the independent common (MAF > 0.05) genetic variants that showed significant associations with 1-year all-cause death (P < 0.05) in 1442 HFpEF patients. Internal cross-validation and subgroup analyses were performed to evaluate the discrimination ability of the HF-PRS. In 209 genes identified by microarray analysis, 69 independent variants (r < 0.1) were selected to develop the HF-PRS model. This model yielded the best discrimination capability for 1-year all-cause mortality with an area under the curve (AUC) of 0.852 (95% CI 0.827-0.877), which outperformed the clinical risk score consisting of 10 significant traditional risk factors for 1-year all-cause mortality (AUC 0.696, 95% CI 0.658-0.734, P = 4 × 10-11), with net reclassification improvement (NRI) of 0.741 (95% CI 0.605-0.877; P < 0.001) and integrated discrimination improvement (IDI) of 0.181 (95% CI 0.145-0.218; P < 0.001). Individuals in the medium and the highest tertile of the HF-PRS had nearly a five-fold (HR = 5.3, 95% CI 2.4-11.9; P = 5.6 × 10-5) and 30-fold (HR = 29.8, 95% CI 14.0-63.5; P = 1.4 × 10-18) increased risk of mortality compared to those in the lowest tertile, respectively. The discrimination ability of the HF-PRS was excellent in cross validation and throughout the subgroups regardless of comorbidities, gender, and patients with or without a history of heart failure. CONCLUSION: The HF-PRS comprising 69 genetic variants provided an improvement of prognostic power over the contemporary risk scores and NT-proBNP in HFpEF patients.