A polygenic risk score of atrial fibrillation improves prediction of lifetime risk for heart failure

Abstract

Aims: Heart failure (HF) has shared genetic architecture with its risk factors: atrial fibrillation (AF), body mass index (BMI), coronary heart disease (CHD), systolic blood pressure (SBP), and type 2 diabetes (T2D). We aim to assess the association and risk prediction performance of risk-factor polygenic risk scores (PRSs) for incident HF and its subtypes in bi-racial populations.

Methods and results: Five PRSs were constructed for AF, BMI, CHD, SBP, and T2D in White participants of the Atherosclerosis Risk in Communities (ARIC) study. The associations between PRSs and incident HF and its subtypes were assessed using Cox models, and the risk prediction performance of PRSs was assessed using C statistics. Replication was performed in the ARIC study Black and Cardiovascular Health Study (CHS) White participants. In 8624 ARIC study Whites, 1922 (31% cumulative incidence) HF cases developed over 30 years of follow-up. PRSs of AF, BMI, and CHD were associated with incident HF (P < 0.001), where PRS_AF showed the strongest association [hazard ratio (HR): 1.47, 95% confidence interval (CI): 1.41-1.53]. Only the addition of PRS_AF to the ARIC study HF risk equation improved C statistics for 10 year risk prediction from 0.812 to 0.829 (∆C: 0.017, 95% CI: 0.009-0.026). The PRS_AF was associated with both incident HF with reduced ejection fraction (HR: 1.43, 95% CI: 1.27-1.60) and incident HF with preserved ejection fraction (HR: 1.46, 95% CI: 1.33-1.62). The associations between PRS_AF and incident HF and its subtypes, as well as the improved risk prediction, were replicated in the ARIC study Blacks and the CHS Whites (P < 0.050). Protein analyses revealed that N-terminal pro-brain natriuretic peptide and other 98 proteins were associated with PRS_AF.

Conclusions: The PRS_AF was associated with incident HF and its subtypes and had significant incremental value over an established HF risk prediction equation.

Keywords: Cohort; Heart failure; Polygenic risk score; Risk prediction.

Figure 1

Distribution of polygenic risk scores (PRSs) for atrial fibrillation (AF), body mass index (BMI), coronary heart disease (CHD), systolic blood pressure (SBP), and type 2 diabetes (T2D) in the Atherosclerosis Risk in Communities (ARIC) study Whites by (A) sex and (B) heart failure status. Distribution of PRS_AF in the ARIC study Blacks and the Cardiovascular Health Study (CHS) Whites by (C) sex and (D) heart failure status.

Figure 2

Kaplan–Meier survival curves for incident heart failure by quintiles of polygenic risk scores for (A) atrial fibrillation (AF), (B) body mass index (BMI), and (C) coronary heart disease (CHD) in Whites from the Atherosclerosis Risk in Communities study. Shaded areas represent 95% confidence intervals, and P values are obtained from log‐rank tests.

Figure 3

Protein pathway analysis in Whites from the Atherosclerosis Risk in Communities study. (A) Volcano plot of 4877 plasma proteins on the polygenic risk score for atrial fibrillation. Significant proteins [false discovery rate (FDR) P value] are shown in red. (B) Significantly enriched (FDR P value <0.05) functional annotations of 99 proteins. (C) Protein–protein interaction (PPI) network of 99 proteins. Colours represent clusters identified in network: Cluster 1 is red, and Cluster 2 is blue. (D) Top 10 hub genes identified in PPI network for having the greatest degree of network connections where colours indicate the protein's connectivity degree ranking in the entire PPI network: red is high, orange is moderate, and yellow is low.