Brunham Liam R
Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, 16 - 1081 Burrard Street, Vancouver, BC, V7L2B3, Canada.
Departments of Medicine and Medical Genetics, University of British Columbia, Vancouver, Canada.
Curr Atheroscler Rep. 2025 Aug 13;27(1):80. doi: 10.1007/s11883-025-01325-8.
Heterozygous Familial Hypercholesterolemia (HeFH) is among the most common genetic conditions worldwide that affects ~ 1 in 300 individuals. HeFH is characterized by increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of coronary artery disease (CAD), but there is a wide spectrum of severity within the HeFH population. This variability in expression is incompletely explained by known risk factors. The purpose of this review is to discuss recent studies that have examined how polygenic risk can modulate the phenotypic expression of HeFH.
Over the past several years, polygenic risk scores (PRS) that summarize information about many genetic variants that influence various traits have been developed. This includes polygenic risk scores for levels of LDL-C and other lipid fractions, CAD, and various other cardio-metabolic traits. In some individuals with a clinical phenotype compatible with HeFH but in whom a pathogenic variant is not present, an elevated PRS for LDL-C may explain the hypercholesterolemia. Among individuals with monogenic HeFH, an elevated PRS for LDL-C or CAD can further exacerbate the clinical phenotype and increase the risk of cardiovascular events. Conversely, a low PRS for these traits can mask the presentation of HeFH by decreasing the clinical severity and thus lead to incomplete phenotypic penetrance of a pathogenic HeFH-causing variant. Although HeFH is a prototypical monogenic condition, recent studies have revealed how the genomic background, as reflected by PRSs, can further modulate the clinical phenotype up or down in severity, thus adding a previously unrecognized level of complexity to monogenic disease. Having identified PRSs that can alter the clinical trajectory of HeFH, the next challenge for the field will be to implement PRS testing into clinical practice to allow clinicians to tailor risk prediction and treatment approaches based on each individual's unique complement of genetic factors.
杂合子家族性高胆固醇血症（HeFH）是全球最常见的遗传疾病之一，每300人中约有1人受其影响。HeFH的特征是低密度脂蛋白胆固醇（LDL-C）水平升高以及冠状动脉疾病（CAD）风险增加，但HeFH人群的严重程度范围很广。已知的风险因素并不能完全解释这种表达的变异性。本综述的目的是讨论最近的研究，这些研究探讨了多基因风险如何调节HeFH的表型表达。
在过去几年中，已经开发出多基因风险评分（PRS），用于总结有关影响各种性状的许多基因变异的信息。这包括LDL-C和其他脂质成分水平、CAD以及各种其他心血管代谢性状的多基因风险评分。在一些临床表型与HeFH相符但不存在致病变异的个体中，LDL-C的PRS升高可能解释了高胆固醇血症。在单基因HeFH个体中，LDL-C或CAD的PRS升高可进一步加重临床表型并增加心血管事件的风险。相反，这些性状的低PRS可通过降低临床严重程度来掩盖HeFH的表现，从而导致致病HeFH变异的表型不完全外显。尽管HeFH是一种典型的单基因疾病，但最近的研究揭示了由PRS反映的基因组背景如何进一步上调或下调临床表型的严重程度，从而为单基因疾病增加了一个以前未被认识到的复杂层面。在确定了可以改变HeFH临床病程的PRS后，该领域的下一个挑战将是将PRS检测应用于临床实践，以便临床医生能够根据每个个体独特的遗传因素组合来调整风险预测和治疗方法。
