Expansion of mutation-driven haematopoietic clones is associated with insulin resistance and low HDL-cholesterol in individuals with obesity

Aging is associated with clonal hematopoiesis (CH) caused by somatic mutations in blood cell progenitors. Mutations with ≥2% variant allele frequency (VAF), known as clonal hematopoiesis of indeterminate potential (CHIP) mutations, have been linked to risk of hematological malignancies and cardiovascular disease. Using an ultrasensitive single-molecule molecular inversion probe (smMIP) sequencing assay, we identified clonal hematopoiesis driver mutations (CHDMs) in a set of established CH driver genes in individuals with obesity from the Swedish Obese Subjects study. In cross-sectional setting, with samples from 1050 individuals, we identified 273 candidate CHDMs in 216 individuals, with a VAF ranging from 0.01% to 31.15% and with clone sizes and prevalence increasing with age. Longitudinal analysis over 20 years in 40 individuals showed that small clones may grow over time and become CHIP. Greater speed of clone growth was associated with insulin resistance (R=0.04, P=0.025) and low circulating levels of high-density lipoprotein-cholesterol (R=-0.68, P=1.74E-05), suggesting that dysfunctional metabolism may accelerate expansion of CH.