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R2_CHIP_T2D_TOPMED_Supplement_v8.1.2023_CLEAN (2).pdf (221.55 kB)

Clonal Hematopoiesis of Indeterminate Potential (CHIP) and incident type 2 diabetes (T2D) risk

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posted on 2023-09-27, 17:43 authored by Deirdre K. Tobias, Alisa K. Manning, Jennifer Wessel, Sridharan Raghavan, Kenneth E. Westerman, Alexander G. Bick, Daniel DiCorpo, Eric A. Whitsel, Jason Collins, Adolfo Correa, L. Adrienne Cupples, Josée Dupuis, Mark O Goodarzi, Xiuqing Guo, Barbara Howard, Leslie A. Lange, Simin Liu, Laura M. Raffield, Alex P. Reiner, Stephen S. Rich, Kent D. Taylor, Lesley Tinker, James G. Wilson, Peitao Wu, April P. Carson, Ramachandran S. Vasan, Myriam Fornage, Bruce M. Psaty, Charles Kooperberg, Jerome I. Rotter, James Meigs, JoAnn E Manson

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 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 NHLBI Trans-omics for Precision Medicine (TOPMed) prospective cohorts. We analyzed 17,637 participants from 6 cohorts, without prior T2D, cardiovascular disease, or cancer. We evaluated baseline CHIP vs. no CHIP prevalence with incident T2D, including associations with DNMT3A, TET2, ASXL1, JAK2, and TP53 variants. We estimated multivariable-adjusted hazard ratios and 95% confidence intervals (HR [CI]) adjusted for age, sex, body mass index, smoking, alcohol, education, self-reported race/ethnicity, and combined cohorts’ estimates via fixed effects meta-analysis.

Results: Mean age was 63.4 years (SD=11.5), 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 a 23% (1.04, 1.45) higher risk of T2D than those with no CHIP. Specifically, TET2 (HR=1.48; 1.05, 2.08) and ASXL1 (HR=1.76; 1.03, 2.99) mutations were at higher T2D risk, and DNMT3A was non-significant (HR=1.15; 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.

Funding

Funding: JM, JD, DD, and PW are partially supported by NIDDK U01 DK078616. JM and DD are partially supported by U01 DK105554. JC is supported by T32 HL129982. 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. Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). Genome Sequencing for “NHLBI TOPMed: Whole Genome Sequencing and Related Phenotypes in the Coronary Artery Risk Development in Young Adults Study” (phs001612) was performed at the Baylor College of Medicine Human Genome Sequencing Center (HHSN268201600033I). Genome Sequencing for “NHLBI TOPMed: Whole Genome Sequencing and Related Phenotypes in the Cardiovascular Health Study” (phs001368) was performed at the Broad Institute Genomics Platform (HHSN268201600034I) and supported by HL105756 (CHARGE). Genome Sequencing for “NHLBI TOPMed: Whole Genome Sequencing and Related Phenotypes in the Framingham Heart Study” (phs000974) was performed at the Broad Institute Genomics Platform (3U54HG003067-12S2). Genome Sequencing for “NHLBI TOPMed: Whole Genome Sequencing and Related Phenotypes in the Jackson Heart Study” (phs000964) was performed at the New York Genome Center Genomics (HHSN268201100037C). Genome Sequencing for “NHLBI TOPMed: Whole Genome Sequencing and Related Phenotypes in the Multi-Ethnic Study of Atherosclerosis Study” (phs001416) was performed at the Broad Institute Genomics Platform (3U54HG003067-13S1). Genome Sequencing for “NHLBI TOPMed: Whole Genome Sequencing and Related Phenotypes in the Women's Health Initiative Study” (phs001237) was performed at the Broad Institute Genomics Platform (HHSN268201500014C). Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics

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