Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease

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; Pradeep Natarajan; Karen N Conneely

doi:10.1038/s41467-022-33093-3

Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease

Nat Commun. 2022 Sep 12;13(1):5350. doi: 10.1038/s41467-022-33093-3.

Authors

M D Mesbah Uddin^{1

2}, Ngoc Quynh H Nguyen³, Bing Yu³, Jennifer A Brody⁴, Akhil Pampana¹, Tetsushi Nakao^{1

2

5

6}, Myriam Fornage^{7

8}, Jan Bressler^{3

8}, Nona Sotoodehnia⁴, Joshua S Weinstock⁹, Michael C Honigberg^{1

2}, Daniel Nachun¹⁰, Romit Bhattacharya^{1

2

11}, Gabriel K Griffin^{12

13

14}, Varuna Chander^{15

16}, Richard A Gibbs^{15

16}, Jerome I Rotter¹⁷, Chunyu Liu^{18

19}, Andrea A Baccarelli²⁰, Daniel I Chasman^{11

21}, Eric A Whitsel^{22

23}, Douglas P Kiel^{11

24

25

26}, Joanne M Murabito^{19

27}, Eric Boerwinkle^{3

8

15}, Benjamin L Ebert^{5

28}, Siddhartha Jaiswal¹⁰, James S Floyd^{4

29}, Alexander G Bick³⁰, Christie M Ballantyne³¹, Bruce M Psaty^{4

29

32}, Pradeep Natarajan^#^{33

34

35}, Karen N Conneely^#³⁶

Affiliations

¹ Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
² Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA.
³ Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
⁴ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, 98101, USA.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
⁶ Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.
⁷ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
⁸ Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
⁹ Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, 48109, USA.
¹⁰ Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
¹¹ Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
¹² Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
¹³ Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA.
¹⁴ Epigenomics Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
¹⁵ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
¹⁶ Department of Genetics and Genomics, Baylor College of Medicine, Houston, TX, 77030, USA.
¹⁷ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
¹⁸ Department of Biostatistics, School of Public Health, Boston University, Boston, MA, 02118, USA.
¹⁹ Framingham Heart Study, Boston University and NHLBI/NIH, Framingham, MA, 01702, USA.
²⁰ Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, 10032, USA.
²¹ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA.
²² Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27516, USA.
²³ Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, 27516, USA.
²⁴ Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, 02131, USA.
²⁵ Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
²⁶ Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
²⁷ Department of Medicine, Section of General Internal Medicine, Boston University School of Medicine and Boston Medical Center, Boston, MA, 02118, USA.
²⁸ Howard Hughes Medical Institute, Boston, MA, 20815, USA.
²⁹ Department of Epidemiology, University of Washington, Seattle, WA, 98101, USA.
³⁰ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
³¹ Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.
³² Department of Health Systems and Population Health, University of Washington, Seattle, WA, 98101, USA.
³³ Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. pnatarajan@mgh.harvard.edu.
³⁴ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA. pnatarajan@mgh.harvard.edu.
³⁵ Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA. pnatarajan@mgh.harvard.edu.
³⁶ Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA. kconnee@emory.edu.

^# Contributed equally.

Abstract

Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.

Publication types

Research Support, Non-U.S. Gov't
Research Support, American Recovery and Reinvestment Act
Research Support, N.I.H., Extramural

MeSH terms

Clonal Hematopoiesis* / genetics
Coronary Artery Disease* / genetics
DNA Methylation / genetics
Hematopoiesis / genetics
Hematopoietic Stem Cells
Humans

Abstract

Publication types

MeSH terms

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