Polygenic risk score for coronary artery disease predicts atherosclerotic cardiovascular disease in familial hypercholesterolemia.

Abstract

Background: Patients with familial hypercholesterolemia (FH) are at increased risk of atherosclerotic cardiovascular disease (ASCVD). However, this risk is heterogeneous, and the contribution of several clinical risk factors has been well demonstrated in this population. The proportion of the risk conferred by the accumulation of common small effect variants in coronary artery disease (CAD) susceptibility genes remains to be determined.

Objective: The objective was to determine if a weighted polygenic risk score (PRS) for CAD (PRS_CAD) is associated with ASCVD risk in patients with heterozygous FH (HeFH).

Methods: This study included 1886 participants with HeFH from 3 independent cohorts: the FH Canada national registry, the UK Biobank, and the Montreal Clinical Research Institute FH cohort. The lifelong ASCVD risk was compared between groups using Kaplan-Meier estimates and Cox proportional hazards regression models.

Results: The group with a high PRS_CAD (>75th percentile) had a ∼2-fold increased risk of ASCVD compared to those with a lower PRS_CAD (≤75th percentile) (HR 1.92 (1.55-2.37), P < .0001). The effect of the PRS_CAD on ASCVD risk remained significant after correction for clinical risk factors (P = .0002). This association was similar between women and men (P interaction = .68), between genetic and clinical FH (P interaction = .48), between cohorts (P interaction = .39), and between the type of PRS (P interaction = .81).

Conclusion: We demonstrated in the largest study to date that the use of a PRS_CAD allowed us to further refine risk stratification in HeFH. Further studies are needed to evaluate the clinical value of adding the PRS_CAD to current risk prediction tools.