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

Lay Summary We performed integrated analyses of mRNA transcriptional and genetic data to construct an HF-PRS comprised of 69 genetic variants in 1442 HFpEF patients from the China PEACE 5p-HF study. We found that the HF-PRS yielded a satisfactory discrimination capability with an AUC of 0.852, which outperformed the clinical risk score consisting of 10 significant traditional risk factors by 15.6% for 1-year all-cause mortality. 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 history of heart failure. 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 x 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 x 10(-5)) and 30-fold (HR = 29.8, 95% CI 14.0-63.5; P = 1.4 x 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.