Clonal Hematopoiesis Is Associated With Higher Risk of Stroke

Author:

Bhattacharya Romit123ORCID,Zekavat Seyedeh M.124ORCID,Haessler Jeffrey5,Fornage Myriam67ORCID,Raffield Laura8ORCID,Uddin Md Mesbah12ORCID,Bick Alexander G.9ORCID,Niroula Abhishek21011ORCID,Yu Bing7ORCID,Gibson Christopher111213ORCID,Griffin Gabriel11,Morrison Alanna C.7ORCID,Psaty Bruce M.141516ORCID,Longstreth William T.1718,Bis Joshua C.19ORCID,Rich Stephen S.20ORCID,Rotter Jerome I.21ORCID,Tracy Russell P.22,Correa Adolfo23ORCID,Seshadri Sudha242526,Johnson Andrew2527ORCID,Collins Jason M.28ORCID,Hayden Kathleen M.29ORCID,Madsen Tracy E.3031ORCID,Ballantyne Christie M.32ORCID,Jaiswal Siddhartha33ORCID,Ebert Benjamin L.1134ORCID,Kooperberg Charles4ORCID,Manson JoAnn E.35ORCID,Whitsel Eric A.3627ORCID,Natarajan Pradeep123ORCID,Reiner Alexander P.37ORCID,

Affiliation:

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, The University of Texas Health Science Center at Houston. (M.F.)

7. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston. (M.F., B.Y., A.C.M.)

8. Department of Genetics (L.R.)

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, University of Washington, Seattle. (B.M.P.)

15. Cardiovascular Health Research Unit, Department of Epidemiology, University of Washington, Seattle. (B.M.P.)

16. Cardiovascular Health Research Unit, Department of Health Services, University of Washington, Seattle. (B.M.P.)

17. Department of Neurology, University of Washington, Seattle. (W.T.L.)

18. Department of Epidemiology, University of Washington, Seattle. (W.T.L.)

19. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle. (J.C.B.)

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, University of North Carolina at Chapel Hill.(J.M.C.)

29. Department of Social Sciences and Health Policy, Wake Forest School of Medicine, Winston-Salem, NC (K.M.H.).

30. Department of Emergency Medicine, Brown University, Providence, RI. (T.E.M.)

31. Department of Epidemiology, Brown University, Providence, RI. (T.E.M.)

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, University of North Carolina at Chapel Hill. (E.A.W.)

37. Department of Epidemiology, University of Washington, Seattle. (A.P.R.)

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Advanced and Specialised Nursing,Cardiology and Cardiovascular Medicine,Clinical Neurology

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