Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia

J Am Coll Cardiol. 2019 Jul 30;74(4):512-522. doi: 10.1016/j.jacc.2019.05.043.


Background: A pathogenic variant in LDLR, APOB, or PCSK9 can be identified in 30% to 80% of patients with clinically-diagnosed familial hypercholesterolemia (FH). Alternatively, ∼20% of clinical FH is thought to have a polygenic cause. The cardiovascular disease (CVD) risk associated with polygenic versus monogenic FH is unclear.

Objectives: This study evaluated the effect of monogenic and polygenic causes of FH on premature (age <55 years) CVD events in patients with clinically diagnosed FH.

Methods: Targeted sequencing of genes known to cause FH as well as common genetic variants was performed to calculate polygenic scores in patients with "possible," "probable," or "definite" FH, according to Dutch Lipid Clinic Network Criteria (n = 626). Patients with a polygenic score ≥80th percentile were considered to have polygenic FH. We examined the risk of unstable angina, myocardial infarction, coronary revascularization, or stoke.

Results: A monogenic cause of FH was associated with significantly greater risk of CVD (adjusted hazard ratio: 1.96; 95% confidence interval: 1.24 to 3.12; p = 0.004), whereas the risk of CVD in patients with polygenic FH was not significantly different compared with patients in whom no genetic cause of FH was identified. However, the presence of an elevated low-density lipoprotein cholesterol (LDL-C) polygenic risk score further increased CVD risk in patients with monogenic FH (adjusted hazard ratio: 3.06; 95% confidence interval: 1.56 to 5.99; p = 0.001).

Conclusions: Patients with monogenic FH and superimposed elevated LDL-C polygenic risk scores have the greatest risk of premature CVD. Genetic testing for FH provides important prognostic information that is independent of LDL-C levels.

Keywords: LDL; atherosclerosis; coronary artery disease; genetic testing; low-density lipoprotein.

Publication types

  • Comparative Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Atherosclerosis / epidemiology
  • Atherosclerosis / genetics*
  • Cardiovascular Diseases / epidemiology
  • Cardiovascular Diseases / genetics
  • Female
  • Genetic Variation
  • Humans
  • Hyperlipoproteinemia Type II / complications*
  • Hyperlipoproteinemia Type II / genetics*
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Multifactorial Inheritance*
  • Prospective Studies
  • Risk Assessment