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

Author:

Han Yi1,Lu Jiapeng1,Chen Bowang1,Li Xi1,Dai Hao1,Zhang Lihua1ORCID,Yan Xiaofang1,Liu Jiamin1,Zhang Haibo1,Fu Xin2,Yu Qin3,Ren Jie4,Cui Hanbin5,Gao Yan1ORCID,Li Jing1ORCID

Affiliation:

1. National Clinical Research Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Fuwai Hospital , 167 Beilishi Road, Beijing, 100037 , China

2. Department of Cardiovascular Medicine, The First Affiliated Hospital of Zhengzhou University , 1 Jianshe East Road, Zhengzhou , China

3. Department of Cardiology, Affiliated Zhongshan Hospital of Dalian University , 6 Jiefang Street, Zhongshan District, Dalian , China

4. Department of Cardiovascular Medicine, First Affiliated Hospital of Xi’an Jiaotong University , 277 Yanta West Road, Yanta District, Xian , China

5. Department of Cardiology, Ningbo First Hospital, Ningbo University , 59 Liuting Street, Haishu District, Ningbo , China

Abstract

Abstract 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.

Funder

National Key Technology R&D Program

Ministry of Science and Technology of China

CAMS Innovation Fund for Medical Sciences

Beijing Nova Program

Publisher

Oxford University Press (OUP)

Subject

Cardiology and Cardiovascular Medicine,Epidemiology

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