Paquette Martine, Trinder Mark, Ruel Isabelle, Guay Simon-Pierre, Hegele Robert A, Genest Jacques, Brunham Liam R, Baass Alexis
Lipids, Nutrition, and Cardiovascular Prevention Clinic of the Montreal Clinical Research Institute, Montreal Québec, Canada (Paquette, Baass).
Faculty of Medicine, University of British Columbia, Centre for Heart and Lung Innovation, Department of Medicine, University of British Columbia, Vancouver British Columbia, Canada (Trinder, Brunham).
J Clin Lipidol. 2025 May-Jun;19(3):595-604. doi: 10.1016/j.jacl.2025.01.004. Epub 2025 Jan 31.
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.
The objective was to determine if a weighted polygenic risk score (PRS) for CAD (PRS) is associated with ASCVD risk in patients with heterozygous FH (HeFH).
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.
The group with a high PRS (>75th percentile) had a ∼2-fold increased risk of ASCVD compared to those with a lower PRS (≤75th percentile) (hazard ratio 1.92 (1.55-2.37), P < .0001). The effect of the PRS 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).
We demonstrated in the largest study to date that the use of a PRS allowed us to further refine risk stratification in HeFH. Further studies are needed to evaluate the clinical value of adding the PRS to current risk prediction tools.
家族性高胆固醇血症（FH）患者发生动脉粥样硬化性心血管疾病（ASCVD）的风险增加。然而，这种风险是异质性的，并且几种临床风险因素在该人群中的作用已得到充分证实。冠状动脉疾病（CAD）易感基因中常见的小效应变异积累所赋予的风险比例仍有待确定。
目的是确定CAD的加权多基因风险评分（PRS）是否与杂合子FH（HeFH）患者的ASCVD风险相关。
本研究纳入了来自3个独立队列的1886名HeFH参与者：加拿大FH国家登记处、英国生物银行和蒙特利尔临床研究所FH队列。使用Kaplan-Meier估计和Cox比例风险回归模型比较各组之间的终生ASCVD风险。
与PRS较低（≤第75百分位数）的组相比，PRS较高（>第75百分位数）的组发生ASCVD的风险增加了约2倍（风险比1.92（1.55-2.37），P<.0001）。在校正临床风险因素后，PRS对ASCVD风险的影响仍然显著（P=.0002）。这种关联在男性和女性之间（P交互作用=.68）、遗传型和临床型FH之间（P交互作用=.48）、队列之间（P交互作用=.39）以及PRS类型之间（P交互作用=.81）相似。
我们在迄今为止最大的研究中证明，可以使用PRS进一步完善HeFH的风险分层。需要进一步研究以评估将PRS添加到当前风险预测工具中的临床价值。
