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

Martine Paquette1, Simon-Pierre Guay2, Alexis Baass1,3

  • 1Genetic Dyslipidemias Clinic of the Montreal Clinical Research Institute, Montreal.

Current Opinion in Lipidology
|February 28, 2026
PubMed

Insights

Polygenic risk scores (PRS) can help assess cardiovascular disease risk in familial hypercholesterolemia (FH). While PRS for low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) have roles, PRS for coronary artery disease (CAD) shows independent predictive value in monogenic FH.

Area of Science:

  • Cardiovascular Genetics
  • Pharmacogenomics
  • Precision Medicine

Background:

  • Familial hypercholesterolemia (FH) presents significant clinical challenges in risk assessment.
  • Polygenic risk scores (PRS) offer a method to evaluate genetic susceptibility for lipoprotein traits and coronary artery disease (CAD).

Purpose of the Study:

  • To review the potential applications of PRS in managing patients with FH.
  • To explore the utility of PRS in diagnosis and cardiovascular risk stratification within FH cohorts.

Main Methods:

  • Review of recent studies investigating the role of PRS in FH.
  • Analysis of PRS for lipoprotein(a), LDL-C, and CAD in relation to cardiovascular outcomes and phenotype.
  • Evaluation of PRS for incremental predictive value over clinical variables.

Main Results:

  • High PRS for lipoprotein(a) can mimic FH phenotype in variant-negative cases; high LDL-C PRS explains a larger proportion.
  • Cardiovascular and type 2 diabetes risks differ between polygenic and monogenic FH.
  • A PRS for CAD, but not LDL-C or lipoprotein(a), independently predicted lifelong cardiovascular disease in monogenic FH.

Conclusions:

  • PRS show potential for diagnostic use and cardiovascular risk stratification in FH.
  • Further research is needed to confirm if PRS provide added predictive value beyond conventional clinical variables before widespread clinical implementation.
Abstract

Keywords:
cardiovascular diseasefamilial hypercholesterolemialow-density lipoprotein cholesterolpolygenic risk scorerisk stratification

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