Polygenic risk scores in familial hypercholesterolemia. Do they have a role?

Risk assessment in patients with familial hypercholesterolemia (FH) remains an important clinical challenge. The polygenic susceptibility for plasma lipoprotein traits or coronary artery disease (CAD) can be assessed by polygenic risk scores (PRS). The purpose of this review is to discuss the potential roles of PRS in the context of FH management. Recent studies suggested that a high PRS for lipoprotein(a) falsely explains the phenotype in a fifth of variant-negative FH patients, whereas a larger proportion can be explained by high low-density lipoprotein cholesterol (LDL-C) PRS. The cardiovascular risk, but also the risk of type 2 diabetes, is different in patients with polygenic hypercholesterolemia compared to monogenic FH. Lastly, it has been shown that a PRS for CAD, but not for LDL-C or lipoprotein(a), was associated with increased lifelong incidence of cardiovascular disease in patients with monogenic FH, independently of clinical variables. Several studies have explored the potential clinical relevance of PRS in FH, including for diagnostic purpose and in cardiovascular risk stratification. Prior to implementation in clinical practice for cardiovascular risk stratification, future studies in FH should determine whether the polygenic information offers incremental predictive value over conventional clinical variables.