Romit Bhattacharya1,2,3, Seyedeh M Zekavat1,2,4, Jeffrey Haessler5, Myriam Fornage6,7, Laura Raffield8, Md Mesbah Uddin1,2, Alexander G Bick9, Abhishek Niroula2,10,11, Bing Yu7, Christopher Gibson11, Gabriel Griffin12,13, Alanna C Morrison1,7, Bruce M Psaty14,15,16, William T Longstreth17,18, Joshua C Bis19, Stephen S Rich20, Jerome I Rotter21, Russell P Tracy22, Adolfo Correa23, Sudha Seshadri24,25,26, Andrew Johnson25,27, Jason M Collins28, Kathleen M Hayden29, Tracy E Madsen30,31, Christie M Ballantyne32, Siddhartha Jaiswal33, Benjamin L Ebert11,34, Charles Kooperberg5, JoAnn E Manson35, Eric A Whitsel36,27, Pradeep Natarajan1,2,3, Alexander P Reiner37. 1. Cardiovascular Research Center, Massachusetts General Hospital, Boston (R.B., S.M.Z., M.M.U., P.N.). 2. Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, MA (R.B., S.M.Z., M.M.U., A.N., P.N.). 3. Department of Medicine, Harvard Medical School, Boston, MA (R.B., P.N.). 4. Yale School of Medicine, New Haven, CT (S.M.Z.). 5. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (J.H., C.K.). 6. Brown Foundation Institute of Molecular Medicine, McGovern Medical School (M.F.), The University of Texas Health Science Center at Houston. 7. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health (M.F., B.Y., A.C.M.), The University of Texas Health Science Center at Houston. 8. Department of Genetics (L.R.), University of North Carolina at Chapel Hill. 9. Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (A.G.B.). 10. Department of Laboratory Medicine, Lund University, Sweden (A.N.). 11. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA (A.N., C.G., B.L.E.). 12. Department of Pathology, Brigham and Women's Hospital, Boston, MA (G.G.). 13. Epigenomics Program, Broad Institute of MIT and Harvard, Cambridge, MA (G.G.). 14. Cardiovascular Health Research Unit, Department of Medicine (B.M.P.), University of Washington, Seattle. 15. Cardiovascular Health Research Unit, Department of Epidemiology (B.M.P.), University of Washington, Seattle. 16. Cardiovascular Health Research Unit, Department of Health Services (B.M.P.), University of Washington, Seattle. 17. Department of Neurology (W.T.L.), University of Washington, Seattle. 18. Department of Epidemiology (W.T.L.), University of Washington, Seattle. 19. Cardiovascular Health Research Unit, Department of Medicine (J.C.B.), University of Washington, Seattle. 20. Center for Public Health Genomics, University of Virginia, Charlottesville (S.S.R.). 21. Department of Pediatrics, Institute for Translational Genomics and Population Sciences, The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA (J.I.R.). 22. Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington (R.P.T.). 23. The Jackson Heart Study, University of Mississippi Medical Center (A.C.). 24. Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio (S.S.). 25. Boston University and the NHLBI's Framingham Heart Study, MA (S.S., A.J.). 26. Department of Neurology, Boston University School of Medicine, MA (S.S.). 27. Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, MA (A.J., E.A.W.). 28. Department of Epidemiology, Gillings School of Global Public Health (J.M.C.), University of North Carolina at Chapel Hill. 29. Department of Social Sciences and Health Policy, Wake Forest School of Medicine, Winston-Salem, NC (K.M.H.). 30. Departments of Emergency Medicine (T.E.M.), Brown University, Providence, RI. 31. Epidemiology (T.E.M.), Brown University, Providence, RI. 32. Department of Medicine, Baylor College of Medicine, Houston, TX (C.M.B.). 33. Department of Pathology, University School of Medicine, CA (S.J.). 34. Howard Hughes Medical Institute, Boston, MA (B.L.E.). 35. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.E.M.). 36. Department of Medicine, School of Medicine (E.A.W.), University of North Carolina at Chapel Hill. 37. Department of Epidemiology (A.P.R.), University of Washington, Seattle.
Abstract
BACKGROUND AND PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke. METHODS: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (DNMT3A, TET2, and ASXL1) with any stroke, ischemic stroke, and hemorrhagic stroke. RESULTS: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; P=0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; P=0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke. CONCLUSIONS: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.
BACKGROUND AND PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke. METHODS: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (DNMT3A, TET2, and ASXL1) with any stroke, ischemic stroke, and hemorrhagic stroke. RESULTS: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; P=0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; P=0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke. CONCLUSIONS: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.
Authors: Alejandro Carrillo-Jimenez; Özgen Deniz; Maria Victoria Niklison-Chirou; Rocio Ruiz; Karina Bezerra-Salomão; Vassilis Stratoulias; Rachel Amouroux; Ping Kei Yip; Anna Vilalta; Mathilde Cheray; Alexander Michael Scott-Egerton; Eloy Rivas; Khadija Tayara; Irene García-Domínguez; Juan Garcia-Revilla; Juan Carlos Fernandez-Martin; Ana Maria Espinosa-Oliva; Xianli Shen; Peter St George-Hyslop; Guy Charles Brown; Petra Hajkova; Bertrand Joseph; Jose Luis Venero; Miguel Ramos Branco; Miguel Angel Burguillos Journal: Cell Rep Date: 2019-10-15 Impact factor: 9.423
Authors: Alexander G Bick; James P Pirruccello; Gabriel K Griffin; Namrata Gupta; Stacey Gabriel; Danish Saleheen; Peter Libby; Sekar Kathiresan; Pradeep Natarajan Journal: Circulation Date: 2019-11-11 Impact factor: 29.690
Authors: Thomas G Brott; Jonathan L Halperin; Suhny Abbara; J Michael Bacharach; John D Barr; Ruth L Bush; Christopher U Cates; Mark A Creager; Susan B Fowler; Gary Friday; Vicki S Hertzberg; E Bruce McIff; Wesley S Moore; Peter D Panagos; Thomas S Riles; Robert H Rosenwasser; Allen J Taylor; Alice K Jacobs; Sidney C Smith; Jeffery L Anderson; Cynthia D Adams; Nancy Albert; Christopher E Buller; Mark A Creager; Steven M Ettinger; Robert A Guyton; Jonathan L Halperin; Judith S Hochman; Sharon Ann Hunt; Harlan M Krumholz; Frederick G Kushner; Bruce W Lytle; Rick A Nishimura; E Magnus Ohman; Richard L Page; Barbara Riegel; William G Stevenson; Lynn G Tarkington; Clyde W Yancy Journal: Catheter Cardiovasc Interv Date: 2011-02-03 Impact factor: 2.692
Authors: Siddhartha Jaiswal; Pradeep Natarajan; Alexander J Silver; Christopher J Gibson; Alexander G Bick; Eugenia Shvartz; Marie McConkey; Namrata Gupta; Stacey Gabriel; Diego Ardissino; Usman Baber; Roxana Mehran; Valentin Fuster; John Danesh; Philippe Frossard; Danish Saleheen; Olle Melander; Galina K Sukhova; Donna Neuberg; Peter Libby; Sekar Kathiresan; Benjamin L Ebert Journal: N Engl J Med Date: 2017-06-21 Impact factor: 91.245
Authors: Marcus A Florez; Brandon T Tran; Trisha K Wathan; James DeGregori; Eric M Pietras; Katherine Y King Journal: Cell Stem Cell Date: 2022-06-02 Impact factor: 25.269
Authors: Amer M Zeidan; Jan Philipp Bewersdorf; Rena Buckstein; Mikkael A Sekeres; David P Steensma; Uwe Platzbecker; Sanam Loghavi; Jacqueline Boultwood; Rafael Bejar; John M Bennett; Uma Borate; Andrew M Brunner; Hetty Carraway; Jane E Churpek; Naval G Daver; Matteo Della Porta; Amy E DeZern; Fabio Efficace; Pierre Fenaux; Maria E Figueroa; Peter Greenberg; Elizabeth A Griffiths; Stephanie Halene; Robert P Hasserjian; Christopher S Hourigan; Nina Kim; Tae Kon Kim; Rami S Komrokji; Vijay Kutchroo; Alan F List; Richard F Little; Ravi Majeti; Aziz Nazha; Stephen D Nimer; Olatoyosi Odenike; Eric Padron; Mrinal M Patnaik; Gail J Roboz; David A Sallman; Guillermo Sanz; Maximilian Stahl; Daniel T Starczynowski; Justin Taylor; Zhuoer Xie; Mina Xu; Michael R Savona; Andrew H Wei; Omar Abdel-Wahab; Valeria Santini Journal: Leukemia Date: 2022-10-20 Impact factor: 12.883
Authors: Pradeep Natarajan; Karen N Conneely; M D Mesbah Uddin; Ngoc Quynh H Nguyen; Bing Yu; Jennifer A Brody; Akhil Pampana; Tetsushi Nakao; Myriam Fornage; Jan Bressler; Nona Sotoodehnia; Joshua S Weinstock; Michael C Honigberg; Daniel Nachun; Romit Bhattacharya; Gabriel K Griffin; Varuna Chander; Richard A Gibbs; Jerome I Rotter; Chunyu Liu; Andrea A Baccarelli; Daniel I Chasman; Eric A Whitsel; Douglas P Kiel; Joanne M Murabito; Eric Boerwinkle; Benjamin L Ebert; Siddhartha Jaiswal; James S Floyd; Alexander G Bick; Christie M Ballantyne; Bruce M Psaty Journal: Nat Commun Date: 2022-09-12 Impact factor: 17.694