<b>Clonal Hematopoiesis of Indeterminate Potential (CHIP) and incident type 2 diabetes (T2D) risk</b>

Abstract

<p><b>Objective:</b> 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.</p><p><b>Research Design and Methods:</b> 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 <i>DNMT3A</i>, <i>TET2</i>, <i>ASXL1</i>, <i>JAK2</i>, and <i>TP53</i> 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.</p><p><b>Results: </b>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, <i>TET2</i> (HR=1.48; 1.05, 2.08) and <i>ASXL1</i> (HR=1.76; 1.03, 2.99) mutations were at higher T2D risk, and <i>DNMT3A</i> was non-significant (HR=1.15; 0.93, 1.43); statistical power was limited for <i>JAK2</i> and <i>TP53</i> analyses.</p><p><b>Conclusions: </b>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.</p>