Human Plasma Proteomic Profile of Clonal Hematopoiesis

Zhi Yu; Amélie Vromman; Ngoc Quynh H Nguyen; Art Schuermans; Thiago Rentz; Shamsudheen K Vellarikkal; Md Mesbah Uddin; Abhishek Niroula; Gabriel Griffin; Michael C Honigberg; Amy E Lin; Christopher J Gibson; Daniel H Katz; Usman Tahir; Shi Fang; Sara Haidermota; Shriienidhie Ganesh; Tajmara Antoine; Joshua Weinstock; Thomas R Austin; Vasan S Ramachandran; Gina M Peloso; Whitney Hornsby; Peter Ganz; JoAnn E Manson; Bernhard Haring; Charles L Kooperberg; Alexander P Reiner; Joshua C Bis; Bruce M Psaty; Yuan-I Min; Adolfo Correa; Leslie A Lange; Wendy S Post; Jerome I Rotter; Stephen S Rich; James G Wilson; Benjamin L Ebert; Bing Yu; Christie M Ballantyne; Josef Coresh; Vijay G Sankaran; Alexander G Bick; Siddhartha Jaiswal; Robert E Gerszten; NHLBI Trans-Omics for Precision Medicine; Peter Libby; Rajat M Gupta; Pradeep Natarajan

doi:10.1101/2023.07.25.550557

Human Plasma Proteomic Profile of Clonal Hematopoiesis

bioRxiv [Preprint]. 2024 Oct 31:2023.07.25.550557. doi: 10.1101/2023.07.25.550557.

Authors

Zhi Yu^{1

2}, Amélie Vromman³, Ngoc Quynh H Nguyen^{4

5}, Art Schuermans^{1

2}, Thiago Rentz³, Shamsudheen K Vellarikkal³, Md Mesbah Uddin^{1

2}, Abhishek Niroula^{1

6

7}, Gabriel Griffin^{1

8

9}, Michael C Honigberg^{1

2

10}, Amy E Lin^{1

3

6}, Christopher J Gibson^{1

6}, Daniel H Katz^{11

12}, Usman Tahir^{10

11}, Shi Fang³, Sara Haidermota^{1

2}, Shriienidhie Ganesh^{1

2}, Tajmara Antoine^{1

2}, Joshua Weinstock^{13

14}, Thomas R Austin^{15

16}, Vasan S Ramachandran^{17

18}, Gina M Peloso¹⁹, Whitney Hornsby^{1

2}, Peter Ganz²⁰, JoAnn E Manson^{21

22}, Bernhard Haring^{23

24}, Charles L Kooperberg²⁵, Alexander P Reiner^{25

26}, Joshua C Bis^{14

27}, Bruce M Psaty^{15

16

26

27}, Yuan-I Min²⁸, Adolfo Correa²⁸, Leslie A Lange²⁹, Wendy S Post³⁰, Jerome I Rotter³¹, Stephen S Rich³², James G Wilson¹¹, Benjamin L Ebert^{1

6

10}, Bing Yu^{4

5}, Christie M Ballantyne³³, Josef Coresh³⁴, Vijay G Sankaran^{1

35

36

37}, Alexander G Bick³⁸, Siddhartha Jaiswal³⁹, Robert E Gerszten^{10

11}; NHLBI Trans-Omics for Precision Medicine; Peter Libby³, Rajat M Gupta³, Pradeep Natarajan^{1

2

10}

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
³ Cardiovascular Division, Brigham and Women's Hospital Heart & Vascular Center, Boston, MA, USA.
⁴ Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁵ Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁷ Department of Laboratory Medicine, Lund University, Lund, Sweden.
⁸ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
⁹ Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁰ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹¹ Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹² Department of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
¹³ Department of Genetics, Stanford University, Stanford, CA, USA.
¹⁴ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
¹⁵ Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
¹⁶ Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹⁷ Department of Medicine, School of Medicine, Boston University, Boston, MA, USA.
¹⁸ Framingham Heart Study, Framingham, MA, USA.
¹⁹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
²⁰ Division of Cardiology, Zuckerberg San Francisco General Hospital and Department of Medicine, University of California, San Francisco, CA, USA.
²¹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²² Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
²³ Department of Medicine III, Saarland University Hospital, Homburg, Germany.
²⁴ Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
²⁵ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²⁶ Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA.
²⁷ Department of Medicine, University of Washington, Seattle, WA, USA.
²⁸ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
²⁹ Department of Medicine, Division of Biomedical Informatics and Personalized Medicine, University of Colorado Anschutz Medical Campus, Denver, CO, USA.
³⁰ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
³¹ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
³² Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
³³ Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
³⁴ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
³⁵ Division of Hematology and Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
³⁶ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
³⁷ Harvard Stem Cell Institute, Cambridge, MA, USA.
³⁸ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
³⁹ Department of Pathology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.

Abstract

Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer novel insights into downstream clinical consequences. Here, we explore such patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 ancestrally diverse participants (3,881 with CHIP) from NHLBI TOPMed and UK Biobank with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2,917 proteins by Olink in UK Biobank), we identified 32 and 345 unique proteins from TOPMed and UK Biobank, respectively, associated with the most prevalent driver genes (DNMT3A, TET2, and ASXL1). These associations showed substantial heterogeneity by driver genes, sex, and race, and were enriched for immune response and inflammation pathways. Mendelian randomization in humans, coupled with ELISA in hematopoietic Tet2-/- vs wild-type mice validation, disentangled causal proteomic perturbations from TET2 CHIP. Lastly, we identified plasma proteins shared between CHIP and CAD.

Publication types

Preprint

Abstract

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