Bing Yu1, Mary B Roberts2, Laura M Raffield3, Seyedeh Maryam Zekavat4, Ngoc Quynh H Nguyen1, Mary L Biggs5, Michael R Brown1, Gabriel Griffin6, Pinkal Desai7, Adolfo Correa8, Alanna C Morrison1, Amil M Shah9, Abhishek Niroula10, Md Mesbah Uddin11, Michael C Honigberg12, Benjamin L Ebert13, Bruce M Psaty14, Eric A Whitsel15, JoAnn E Manson16, Charles Kooperberg17, Alexander G Bick18, Christie M Ballantyne19, Alex P Reiner17, Pradeep Natarajan20, Charles B Eaton21. 1. School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA. 2. Center for Primary Care and Prevention, Brown University, Pawtucket, Rhode Island, USA. 3. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. 4. Yale School of Medicine, New Haven, Connecticut, USA; Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. 5. Department of Biostatistics, University of Washington, Seattle, Washington, USA; Department of Epidemiology, Gillings School of Global Public Health and Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA. 6. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. 7. Division of Hematology and Oncology, Weill Cornell Medical College, New York, New York, USA. 8. Department of Pediatric and Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA. 9. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. 10. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Laboratory Medicine, Lund University, Lund, Sweden. 11. Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. 12. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA; Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. 13. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA; Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 14. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington, USA. 15. Department of Epidemiology, Gillings School of Global Public Health and Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA. 16. Harvard Medical School, Boston, Massachusetts, USA; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. 17. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 18. Division of Genetic Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. 19. Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA. 20. Harvard Medical School, Boston, Massachusetts, USA; Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA; Cardiovascular Disease Initiative of the Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. Electronic address: pnatarajan@mgh.harvard.edu. 21. Department of Epidemiology, Brown University, Providence, Rhode Island, USA; Care New England, Center for Primary Care and Prevention, Pawtucket, Rhode Island, USA; Department of Family Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA. Electronic address: cbeaton51@gmail.com.
Abstract
BACKGROUND: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF). OBJECTIVES: This study sought to evaluate whether CHIP is associated with incident HF. METHODS: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses. RESULTS: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction. CONCLUSIONS: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.
BACKGROUND: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF). OBJECTIVES: This study sought to evaluate whether CHIP is associated with incident HF. METHODS: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses. RESULTS: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction. CONCLUSIONS: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.
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