Limitations of Contemporary Guidelines for Managing Patients at High Genetic Risk of Coronary Artery Disease

J Am Coll Cardiol. 2020 Jun 9;75(22):2769-2780. doi: 10.1016/j.jacc.2020.04.027.


Background: Polygenic risk scores (PRS) for coronary artery disease (CAD) identify high-risk individuals more likely to benefit from primary prevention statin therapy. Whether polygenic CAD risk is captured by conventional paradigms for assessing clinical cardiovascular risk remains unclear.

Objectives: This study sought to intersect polygenic risk with guideline-based recommendations and management patterns for CAD primary prevention.

Methods: A genome-wide CAD PRS was applied to 47,108 individuals across 3 U.S. health care systems. The authors then assessed whether primary prevention patients at high polygenic risk might be distinguished on the basis of greater guideline-recommended statin eligibility and higher rates of statin therapy.

Results: Of 47,108 study participants, the mean age was 60 years, and 11,020 (23.4%) had CAD. The CAD PRS strongly associated with prevalent CAD (odds ratio: 1.4 per SD increase in PRS; p < 0.0001). High polygenic risk (top 20% of PRS) conferred 1.9-fold odds of developing CAD (p < 0.0001). However, among primary prevention patients (n = 33,251), high polygenic risk did not correspond with increased recommendations for statin therapy per the American College of Cardiology/American Heart Association (46.2% for those with high PRS vs. 46.8% for all others, p = 0.54) or U.S. Preventive Services Task Force (43.7% vs. 43.7%, p = 0.99) or higher rates of statin prescriptions (25.0% vs. 23.8%, p = 0.04). An additional 4.1% of primary prevention patients may be recommended for statin therapy if high CAD PRS were considered a guideline-based risk-enhancing factor.

Conclusions: Current paradigms for primary cardiovascular prevention incompletely capture a polygenic susceptibility to CAD. An opportunity may exist to improve CAD prevention efforts by integrating both genetic and clinical risk.

Keywords: coronary artery disease; genetic risk; primary prevention; statin.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Coronary Artery Disease / epidemiology
  • Coronary Artery Disease / genetics*
  • Coronary Artery Disease / therapy
  • Databases, Factual / standards
  • Delivery of Health Care / methods
  • Delivery of Health Care / standards
  • Disease Management*
  • Electronic Health Records / standards*
  • Female
  • Genetic Predisposition to Disease / epidemiology
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Male
  • Middle Aged
  • Multifactorial Inheritance / genetics*
  • Practice Guidelines as Topic / standards*
  • Risk Factors