RT Journal Article
SR Electronic
T1 Expansion of mutation-driven haematopoietic clones is associated with insulin resistance and low HDL-cholesterol in individuals with obesity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.05.12.443095
DO 10.1101/2021.05.12.443095
A1 Rosanne C. van Deuren
A1 Johanna C. Andersson-Assarsson
A1 Felipe M. Kristensson
A1 Marloes Steehouwer
A1 Kajsa Sjöholm
A1 Per-Arne Svensson
A1 Marc Pieterse
A1 Christian Gilissen
A1 Magdalena Taube
A1 Peter Jacobson
A1 Rosie Perkins
A1 Han G. Brunner
A1 Mihai G. Netea
A1 Markku Peltonen
A1 Björn Carlsson
A1 Alexander Hoischen
A1 Lena M.S. Carlsson
YR 2021
UL http://biorxiv.org/content/early/2021/07/09/2021.05.12.443095.abstract
AB Aims Haematopoietic clones caused by somatic mutations with ≥2% variant allele frequency (VAF), known as clonal haematopoiesis of indeterminate potential (CHIP), increase with age and have been linked to risk of haematological malignancies and cardiovascular disease. Recent observations suggest that smaller clones are also associated with adverse clinical outcomes. Our aims were to determine the prevalence of clonal haematopoiesis driven by clones of variable sizes, and to examine the development of clones over time in relation to age and metabolic dysregulation over up to 20 years in individuals with obesity.Methods and Results We used an ultrasensitive single-molecule molecular inversion probe sequencing assay to identify clonal haematopoiesis driver mutations (CHDMs) in blood samples from individuals with obesity from the Swedish Obese Subjects study. In a single-timepoint dataset with samples from 1050 individuals, we identified 273 candidate CHDMs in 216 individuals, with VAF ranging from 0.01% to 31.15% and CHDM prevalence and clone sizes increasing with age. Longitudinal analysis over 20 years in CHDM-positive samples from 40 individuals showed that small clones can grow over time and become CHIP. VAF increased on average by 7% (range -4% to 27%) per year. Rate of clone growth was positively associated with insulin resistance (R=0.40, P=0.025) and low circulating levels of high-density lipoprotein-cholesterol (HDL-C) (R=-0.68, P=1.74E-05).Conclusion Our results show that haematopoietic clones can be detected and monitored before they become CHIP and indicate that insulin resistance and low HDL-C, well-established cardiovascular risk factors, are associated with clonal expansion in individuals with obesity.Translational perspectives Clonal haematopoiesis-driver mutations are somatic mutations in haematopoietic stem cells that lead to clones detectable in peripheral blood. Haematopoietic clones with a variant allele frequency (VAF) ≥2%, known as clonal haematopoiesis of indeterminate potential (CHIP), are recognized as an independent cardiovascular risk factor. Here, we show that smaller clones are prevalent, and also correlate with age. Our longitudinal observations in individuals with obesity over 20 years showed that more than half of all clone-positive individuals show growing clones and clones with VAF <2% can grow and become CHIP. Importantly, clone growth was accelerated in individuals with insulin resistance and low high-density lipoprotein-cholesterol (HDL-C).Translational outlook 1: Haematopoietic clones can be detected and monitored before they become CHIP.Translational outlook 2: The association between insulin resistance and low HDL-C with growth of haematopoietic clones opens the possibility that treatments improving metabolism, such as weight loss, may reduce growth of clones and thereby cardiovascular risk.One Sentence Summary In obesity, the growth rate of mutation-driven haematopoietic clones increased with insulin resistance and low HDL-C, both known risk factors for cardiovascular disease.Competing Interest StatementDr B. Carlsson is employed by and owns stock in AstraZeneca. Dr L. Carlsson has received consulting fees from Johnson & Johnson. Dr M.G. Netea reported being a scientific founder of Trained Therapeutic Discovery and receiving grants from ViiV HealthCare outside the submitted work. No other potential conflict of interest relevant to this article was reported.