Background and Objective: CHIP is the aging-related accumulation of genetic mutations in the hematopoiesis-associated genes of stem cells. CHIP was recently associated with total mortality and atherosclerotic cardiovascular disease. We tested the hypothesis that CHIP is associated with adverse glycemic traits and incident T2D risk.

Methods: This study includes a subset of n=9,704 individuals in the NHLBI Trans-omics for Precision Medicine (TOPMed) project from the Framingham Heart Study (FHS), Jackson Heart Study (JHS), Multi-Ethnic Study of Atherosclerosis (MESA) and Women’s Health Initiative (WHI). We analyzed individuals without a history of T2D, cancer, or cardiovascular disease, and collected blood for fasting glycemic traits and CHIP carrier status. CHIP was recently determined from blood DNA-derived whole genome sequencing using the CATK MuTECT2 somatic variant caller in pre-specified leukemogenic driver mutations in candidate clonal expansion genes. We are conducting multivariable linear models examining both cross-sectional associations of CHIP with glycemic traits and survival models for baseline CHIP with incident T2D, adjusting for age, sex, body mass index, smoking, cohort, and family history of diabetes.

Results: Mean (SD) age was FHS = 50 (14), JHS = 55 (13), MESA = 60 (10), and WHI = 66 (7) years. We identified n=460 (4.7%) as CHIP carriers. The most common variant was located in DNMT3A gene (60% of carriers). Among CHIP carriers, the prevalence of having CHIP present in 1 of the 4 genes previously implicated in atherosclerotic heart disease (DNMT3A, TET2, ASXL1, JAK2; Jaiswal, et al, NEJM 2017) was lowest in FHS (75%) and highest in JHS (96%). Results for CHIP in relation to glycemic traits and incident T2D (∼1,500 cases) will be presented in detail. We will additionally present the associations for gene-specific CHIP mutations.

Conclusions: These cutting-edge TOPMed data will elucidate the role of CHIP, a novel aging biomarker, in relation to T2D risk.

Disclosure

D.K. Tobias: None. S. Raghavan: None. A. Bick: None. L. Raffield: None. P. Wu: None. D.A. DiCorpo: None. J. Dupuis: Consultant; Self; Merck Sharp & Dohme Corp. L. Lange: None. J.I. Rotter: None. C.L. Kooperberg: None. J.B. Meigs: Consultant; Self; Quest Diagnostics. J.E. Manson: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (U01DK078616 to J.B.M., J.D., D.A.D., P.W.), (U01DK105554 to J.D., D.A.D.)

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