Author + information
- Received January 15, 2020
- Revision received March 31, 2020
- Accepted April 7, 2020
- Published online June 1, 2020.
- Krishna G. Aragam, MD, MSa,b,c,∗,
- Amanda Dobbyn, PhDd,e,∗,
- Renae Judy, MSf,
- Mark Chaffin, MSb,
- Kumardeep Chaudhary, PhDd,e,
- George Hindy, MD, PhDb,
- Andrew Cagan, BSg,
- Phoebe Finneran, BSc,
- Lu-Chen Weng, PhDb,c,
- Ruth J.F. Loos, PhDd,h,
- Girish Nadkarni, MDd,e,
- Judy H. Cho, MDd,e,i,
- Rachel L. Kember, PhDj,
- Aris Baras, MD, MBAk,
- Jeffrey Reid, PhDk,
- John Overton, PhDk,
- Anthony Philippakis, MD, PhDb,
- Patrick T. Ellinor, MD, PhDb,c,
- Scott T. Weiss, MDl,
- Daniel J. Rader, MDj,
- Steven A. Lubitz, MD, MPHb,c,
- Jordan W. Smoller, MD, ScDa,m,n,
- Elizabeth W. Karlson, MDo,
- Amit V. Khera, MDa,b,
- Sekar Kathiresan, MDa,b,
- Ron Do, PhDd,e,∗∗ (, )@DoGenetics,
- Scott M. Damrauer, MDf,p,† and
- Pradeep Natarajan, MD, MMSca,b,c,∗,† (, )@pnatarajanmd
- aCenter for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- bProgram in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts
- cCardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- dThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
- eDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
- fDepartment of Surgery, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- gResearch Computing, Partners HealthCare, Charlestown, Massachusetts
- hThe Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- iDepartment of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
- jDepartment of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- kRegeneron Genetics Center, Tarrytown, New York
- lDepartment of Medicine, Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- mDepartment of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts
- nStanley Center for Psychiatric Research, Broad Institute, Boston, Massachusetts
- oDepartment of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Boston, Massachusetts
- pCorporal Michael Crescenz VA Medical Center, Philadelphia, Pennsylvania
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.
↵∗ Drs. Aragam and Dobbyn contributed equally to this work.
↵† Drs. Damrauer and Natarajan jointly supervised this work.
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.
- Received January 15, 2020.
- Revision received March 31, 2020.
- Accepted April 7, 2020.
- 2020 American College of Cardiology Foundation
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