Meta-Analysis

. 2023 Nov 1;46(11):1978-1985.

doi: 10.2337/dc23-0805.

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

Deirdre K Tobias^{1

2}, Alisa K Manning^{3

4

5}, Jennifer Wessel⁶, Sridharan Raghavan⁷, Kenneth E Westerman^{3

4

5}, Alexander G Bick⁸, Daniel Dicorpo⁹, Eric A Whitsel¹⁰, Jason Collins¹⁰, Adolfo Correa¹¹, L Adrienne Cupples⁹, Josée Dupuis⁹, Mark O Goodarzi¹², Xiuqing Guo¹³, Barbara Howard¹⁴, Leslie A Lange⁷, Simin Liu¹⁵, Laura M Raffield¹⁶, Alex P Reiner¹⁷, Stephen S Rich¹⁸, Kent D Taylor¹⁹, Lesley Tinker¹⁹, James G Wilson²⁰, Peitao Wu⁹, April P Carson¹¹, Ramachandran S Vasan^{21

22}, Myriam Fornage²³, Bruce M Psaty²⁴, Charles Kooperberg¹⁹, Jerome I Rotter¹³, James Meigs^{25

26}, JoAnn E Manson^{1

27}; TOPMed Diabetes Working Group and National Heart, Lung, and Blood Institute TOPMed Consortium

Affiliations

¹ Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
² Nutrition Department, Harvard T.H. Chan School of Public Health, Boston, MA.
³ Broad Metabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA.
⁴ Harvard Medical School, Boston, MA.
⁵ Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital, Boston, MA.
⁶ Department 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 Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, and Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO.
⁸ Division of Genetic Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
⁹ Department of Biostatistics, Boston University School of Public Health, Boston, MA.
¹⁰ Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
¹¹ Department of Medicine, University of Mississippi Medical Center, Jackson, MS.
¹² Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.
¹³ Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.
¹⁴ MedStar Health Research Institute, Hyattsville, MD.
¹⁵ Center for Global Cardiometabolic Health, Brown University, Providence, RI.
¹⁶ Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
¹⁷ Department of Epidemiology, University of Washington, Seattle, WA.
¹⁸ Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
¹⁹ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA.
²⁰ Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA.
²¹ Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA.
²² University of Texas School of Public Health, San Antonio, TX.
²³ Brown 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.
²⁴ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, WA.
²⁵ Department of Medicine, Harvard Medical School, and Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA.
²⁶ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
²⁷ Epidemiology Department, Harvard T.H. Chan School of Public Health, Boston, MA.

PMID: 37756531
PMCID: PMC10620536
DOI: 10.2337/dc23-0805

Meta-Analysis

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

Deirdre K Tobias et al. Diabetes Care. 2023.

. 2023 Nov 1;46(11):1978-1985.

doi: 10.2337/dc23-0805.

Authors

Affiliations

¹ Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
² Nutrition Department, Harvard T.H. Chan School of Public Health, Boston, MA.
³ Broad Metabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA.
⁴ Harvard Medical School, Boston, MA.
⁵ Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital, Boston, MA.
⁶ Department 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 Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, and Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO.
⁸ Division of Genetic Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
⁹ Department of Biostatistics, Boston University School of Public Health, Boston, MA.
¹⁰ Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
¹¹ Department of Medicine, University of Mississippi Medical Center, Jackson, MS.
¹² Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.
¹³ Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.
¹⁴ MedStar Health Research Institute, Hyattsville, MD.
¹⁵ Center for Global Cardiometabolic Health, Brown University, Providence, RI.
¹⁶ Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
¹⁷ Department of Epidemiology, University of Washington, Seattle, WA.
¹⁸ Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
¹⁹ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA.
²⁰ Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA.
²¹ Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA.
²² University of Texas School of Public Health, San Antonio, TX.
²³ Brown 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.
²⁴ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, WA.
²⁵ Department of Medicine, Harvard Medical School, and Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA.
²⁶ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
²⁷ Epidemiology Department, Harvard T.H. Chan School of Public Health, Boston, MA.

PMID: 37756531
PMCID: PMC10620536
DOI: 10.2337/dc23-0805

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.

PubMed Disclaimer

Conflict of interest statement

Duality of Interest. L.M.R. is a consultant for the TOPMed Administrative Coordinating Center (through Westat). No other potential conflicts of interest relevant to this article were reported.

Figures

**Figure 1**
Presence of CHD-related CHIP mutations and risk of incident T2D among 17,637 National Heart, Lung, and Blood Institute (NHLBI) TOPMed participants. Estimates were adjusted for age (continuous), sex (male/female), BMI (continuous), smoking status (never smoker, former, current), education (less than high school, high school or equivalent, some college, college degree or higher), and self-reported race/ethnicity (White, Black, Native American, Asian American, Hispanic, other); analyses included adjustment for alcohol use for all cohorts except CHS (nondrinker, light [women 1–14 g/day, men 1–28 g/day], moderate [women 15–28 g/day, men 29–42 g/day], heavy [women >28 g/day, men >42 g/day]).

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous