Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Incident Type 2 Diabetes Risk

Author:

Tobias Deirdre K.12ORCID,Manning Alisa K.345,Wessel Jennifer6,Raghavan Sridharan7,Westerman Kenneth E.345,Bick Alexander G.8,Dicorpo Daniel9,Whitsel Eric A.10,Collins Jason10,Correa Adolfo11,Cupples L. Adrienne9,Dupuis Josée9,Goodarzi Mark O.12,Guo Xiuqing13,Howard Barbara14,Lange Leslie A.7,Liu Simin15,Raffield Laura M.16,Reiner Alex P.17,Rich Stephen S.18,Taylor Kent D.19,Tinker Lesley19,Wilson James G.20,Wu Peitao9,Carson April P.21,Vasan Ramachandran S.2223,Fornage Myriam24,Psaty Bruce M.25,Kooperberg Charles19,Rotter Jerome I.13,Meigs James2627,Manson JoAnn E.128,

Affiliation:

1. 1Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA

2. 2Nutrition Department, Harvard T.H. Chan School of Public Health, Boston, MA

3. 3Broad Metabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA

4. 4Harvard Medical School, Boston, MA

5. 5Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital, Boston, MA

6. 6Department of Epidemiology, Richard M. Fairbanks School of Public Health, Department of Medicine, School of Medicine, and Diabetes Translational Research Center, Indiana University, Indianapolis, IN

7. 7Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, and Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO

8. 8Division of Genetic Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN

9. 9Department of Biostatistics, Boston University School of Public Health, Boston, MA

10. 10Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC

11. 11Department of Medicine, University of Mississippi Medical Center, Jackson, MS

12. 12Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA

13. 13Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA

14. 14MedStar Health Research Institute, Hyattsville, MD

15. 15Center for Global Cardiometabolic Health, Brown University, Providence, RI

16. 16Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC

17. 17Department of Epidemiology, University of Washington, Seattle, WA

18. 18Center for Public Health Genomics, University of Virginia, Charlottesville, VA

19. 19Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA

20. 20Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA

21. 21Department of Medicine, University of Mississippi Medical Center, Jackson, MS

22. 22Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA

23. 23University of Texas School of Public Health, San Antonio, TX

24. 24Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX

25. 25Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, WA

26. 26Department of Medicine, Harvard Medical School, and Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA

27. 27Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA

28. 28Epidemiology Department, Harvard T.H. Chan School of Public Health, Boston, MA

Abstract

OBJECTIVE Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D. RESEARCH DESIGN AND METHODS CHIP was derived from whole-genome sequencing of blood DNA in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) prospective cohorts. We performed analysis for 17,637 participants from six cohorts, without prior T2D, cardiovascular disease, or cancer. We evaluated baseline CHIP versus no CHIP prevalence with incident T2D, including associations with DNMT3A, TET2, ASXL1, JAK2, and TP53 variants. We estimated multivariable-adjusted hazard ratios (HRs) and 95% CIs with adjustment for age, sex, BMI, smoking, alcohol, education, self-reported race/ethnicity, and combined cohorts’ estimates via fixed-effects meta-analysis. RESULTS Mean (SD) age was 63.4 (11.5) years, 76% were female, and CHIP prevalence was 6.0% (n = 1,055) at baseline. T2D was diagnosed in n = 2,467 over mean follow-up of 9.8 years. Participants with CHIP had 23% (CI 1.04, 1.45) higher risk of T2D than those with no CHIP. Specifically, higher risk was for TET2 (HR 1.48; CI 1.05, 2.08) and ASXL1 (HR 1.76; CI 1.03, 2.99) mutations; DNMT3A was nonsignificant (HR 1.15; CI 0.93, 1.43). Statistical power was limited for JAK2 and TP53 analyses. CONCLUSIONS CHIP was associated with higher incidence of T2D. CHIP mutations located on genes implicated in CHD and mortality were also related to T2D, suggesting shared aging-related pathology.

Funder

RV is supported in part by the Evans Medical Foundation and the Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine

NIDDK

Publisher

American Diabetes Association

Subject

Advanced and Specialized Nursing,Endocrinology, Diabetes and Metabolism,Internal Medicine

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