Author + information
- Received April 26, 2019
- Revision received August 27, 2019
- Accepted August 27, 2019
- Published online November 18, 2019.
- Amit V. Khera, MD, MSca,b,c,∗ (, )@amitvkhera,
- Heather Mason-Suares, PhDd,
- Deanna Brockman, MSa,c,
- Minxian Wang, PhDc,
- Martin J. VanDenburgh, BAe,
- Ozlem Senol-Cosar, PhDd,f,
- Candace Patterson, BSc,
- Christopher Newton-Cheh, MDa,b,
- Seyedeh M. Zekavat, BScc,
- Julie Pester, BAe,
- Daniel I. Chasman, PhDe,
- Christopher Kabrhel, MDg,h,
- Majken K. Jensen, PhDh,
- JoAnn E. Manson, MD, DrPHe,
- J. Michael Gaziano, MDh,i,j,
- Kent D. Taylor, PhDk,
- Nona Sotoodehnia, MDl,
- Wendy S. Post, MDm,
- Stephen S. Rich, PhDn,
- Jerome I. Rotter, MDk,
- Eric S. Lander, PhDc,o,p,
- Heidi L. Rehm, PhDa,
- Kenney Ng, PhDq,
- Anthony Philippakis, MD, PhDc,
- Matthew Lebo, PhDd,
- Christine M. Albert, MDe,r,∗∗ (, )@CMAlbertEP and
- Sekar Kathiresan, MDs,∗
- aCenter for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts
- bCardiology Division, Massachusetts General Hospital, Boston, Massachusetts
- cCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- dLaboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, Massachusetts
- eDivision of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- fJanssen Pharmaceuticals, Cambridge, Massachusetts
- gDepartment of Emergency Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- hChanning Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- iDivision of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- jDivision of Aging, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- kThe Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California
- lCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington
- mDivision of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
- nCenter for Public Health Genomics, University of Virginia, Charlottesville, Virginia
- oDepartment of Biology, MIT, Cambridge, Massachusetts
- pDepartment of Systems Biology, Harvard Medical School, Boston, Massachusetts
- qCenter for Computational Health, IBM Research, Cambridge, Massachusetts
- rSmidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California
- sVerve Therapeutics, Cambridge, Massachusetts
- ↵∗Address for correspondence:
Dr. Amit V. Khera, Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, CPZN 6.256, Boston, Massachusetts 02114.
- ↵∗Dr. Christine M. Albert, Smidt Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., AHSP 3100, Los Angeles California 90048.
Background Sudden cardiac death occurs in ∼220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection.
Objectives This study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population.
Methods The authors performed whole-exome sequencing in a case-control cohort of 600 adult-onset sudden cardiac death cases and 600 matched controls from 106,098 participants of 6 prospective cohort studies. Observed DNA sequence variants in any of 49 genes with known association to cardiovascular disease were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status. In an independent population of 4,525 asymptomatic adult participants of a prospective cohort study, the authors performed whole-genome sequencing and determined the prevalence of pathogenic or likely pathogenic variants and prospective association with cardiovascular death.
Results Among the 1,200 sudden cardiac death cases and controls, the authors identified 5,178 genetic variants and classified 14 as pathogenic or likely pathogenic. These 14 variants were present in 15 individuals, all of whom had experienced sudden cardiac death—corresponding to a pathogenic variant prevalence of 2.5% in cases and 0% in controls (p < 0.0001). Among the 4,525 participants of the prospective cohort study, 41 (0.9%) carried a pathogenic or likely pathogenic variant and these individuals had 3.24-fold higher risk of cardiovascular death over a median follow-up of 14.3 years (p = 0.02).
Conclusions Gene sequencing identifies a pathogenic or likely pathogenic variant in a small but potentially important subset of adults experiencing sudden cardiac death; these variants are present in ∼1% of asymptomatic adults.
↵∗ Drs. Albert and Kathiresan contributed equally to this work and are joint senior authors.
Support was provided by an institutional grant from the Broad Institute of MIT and Harvard (BroadIgnite, to Dr. Khera), grant 1K08HG010155 from the National Human Genome Research Institute (to Dr. Khera), a Hassenfeld Scholar Award from Massachusetts General Hospital (to Dr. Khera), an institutional grant from the Broad Institute of MIT and Harvard (BroadNext10, to Drs. Philippakis and Kathiresan), a sponsored research agreement from IBM Research (to Drs. Khera, Philippakis, and Kathiresan), grant AHA19SFRN348300063 from the American Heart Association (to Dr. Sotoodehnia), and grants R01HL141989 and R01HL116747 from the National Heart, Lung, and Blood Institute (to Dr. Sotoodehnia). The sudden cardiac death case-control cohort was supported by grants HL-03783, HL-26490, HL-34595, HL-34594, HL-35464, HL-043851, HL-46959, HL-099355, and HL-080467 from the National Heart, Lung, and Blood Institute, and CA-167552, CA-186107, CA-49449CA-34944, CA-40360, CA-47988, CA-55075, CA-87969, and CA-97193 from the National Cancer Institute. The sudden death confirmation was supported by grants from the National Institutes of Health (HL-068070) and Novo Nordisk Foundation, Copenhagen, Denmark. The MESA and the MESA SHARe projects are conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Whole genome sequencing of the MESA cohort was funded through the Trans-Omics for Precision Medicine (TOPMed) Program of the National Heart, Lung, and Blood Institute. General study coordination was provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). Funding agencies had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Dr. Khera has received personal fees from Color Genomics, Navitor Pharmaceuticals, Maze Therapeutics, Amarin Pharmaceuticals, and Novartis Institute for Biomedical Research; and reports a patent related to a genetic risk predictor (20190017119). Dr. Senol-Cosar is an employee of Janssen Pharmaceuticals. Dr. Newton-Cheh has received personal fees from GE Healthcard and Novartis. Dr. Kabrhel’s institution has received grants from Diagnostica Stago, Siemens Healthcare Diagnostics, and Janssen. Dr. Lander serves on the Board of Directors for Codiak BioSciences and Neon Therapeutics; serves on the Scientific Advisory Board of F-Prime Capital Partners and Third Rock Ventures; serves on the Board of Directors of the Innocence Project, Count Me In, and Biden Cancer Initiative; and serves on the Board of Trustees for the Parker Institute for Cancer Immunotherapy. Dr. Ng is an employee of IBM. Dr. Philippakis is a venture partner at GV, a subsidiary of Alphabet Corporation. Dr. Albert has received grants from St. Jude Medical, Abbott, and Roche Diagnostics; and has received personal fees from Myocardia. Dr. Kathiresan is founder and CEO of Verve Therapeutics; is founder of Maze Therapeutics; holds equity in Catabasis and San Therapeutics; has received personal fees from MedGenome, Novo Nordisk, Merck, Eli Lilly, Alnylam, Regeneron, Acceleron, Corvidia, Novartis, Novo Ventures, Ionis, Illumina, Haug Partners, Noble Insights, Leerink Partners, Bayer Healthcare, Color Genomics, MedGenome, Quest, and Medscape; and reports patents related to a method of identifying and treating a person having a pre-disposition to or afflicted with cardiometabolic disease (20180010185) and a genetics risk predictor (20190017119). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. P.J. Schwartz, MD, served as Guest Associate Editor for this paper.
- Received April 26, 2019.
- Revision received August 27, 2019.
- Accepted August 27, 2019.
- 2019 American College of Cardiology Foundation
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