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

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Abstract

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.

Key Words

coronary artery disease
genetic risk
primary prevention
statin

Abbreviations and Acronyms

ACC
American College of Cardiology
AHA
American Heart Association
ASCVD
atherosclerotic cardiovascular disease
AUROC
area under the receiver operating characteristic curve
CAD
coronary artery disease
CI
confidence interval
EHR
electronic health record
FH
familial hypercholesterolemia
GWAS
genome-wide association study
LDL-C
low-density lipoprotein cholesterol
OR
odds ratio
PCE
Pooled Cohort Equations
PRS
polygenic risk score
USPSTF
United States Preventive Services Task Force

Cited by (0)

This publication is solely the responsibility of the authors and does not represent the views of the American Heart Association, National Institutes of Health/National Heart, Lung, and Blood Institute, Department of Veterans Affairs, or the United States government. Dr. Aragam is supported by an award from the American Heart Association Institute for Precision Cardiovascular Medicine (17IFUNP33840012). Dr. Chaffin is supported by a grant from Bayer AG to the Broad Institute focused on the development of therapeutics for cardiovascular disease. Dr. Weiss is supported in part by an NHGRI grant supporting the eMERGE Network (U01HG008685). Dr. Lubitz is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007; has received research support from AstraZeneca and Goldfinch Bio, not related to this work; receives sponsored research support from Bristol-Myers Squibb/Pfizer, Bayer AG, and Boehringer Ingelheim; and has consulted for Bristol-Myers Squibb/Pfizer and Bayer AG. Dr. Smoller is supported in part by an NHGRI grant supporting the eMERGE Network (U01HG008685); and is an unpaid member of the Bipolar/Depression Research Community Advisory Panel of 23andMe. Dr. Karlson is supported in part by an NHGRI grant supporting the eMERGE Network (U01HG008685). Dr. Do is supported by R35GM124836 from the National Institute of General Medical Sciences of the National Institutes of Health, and R01HL139865 from the National Heart, Lung, and Blood Institute of the National Institutes of Health. Dr. Damrauer is supported by the U.S. Department of Veterans Affairs (IK2-CX001780); and has received research support to the University of Pennsylvania from CytoVas LLC and Renalytix AI, not related to this work. Dr. Natarajan is supported by grants from the National Heart, Lung, and Blood Institute (R01HL142711, R01HL148565, R01HL148050), Fondation Leducq (TNE-18CVD04), and Hassenfeld Scholar Award from the Massachusetts General Hospital; has received grant support from Amgen, Apple, and Boston Scientific; and is a scientific advisor to Apple. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Peter Ganz, MD, served as Guest Associate Editor for this paper. P.K. Shah, MD, served as Guest Editor-in-Chief for this paper.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC author instructions page.

Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.

Drs. Aragam and Dobbyn contributed equally to this work.

Drs. Damrauer and Natarajan jointly supervised this work.