Background: Haematopoietic clones caused by somatic mutations with ≥2% variant allele frequency (VAF) increase with age and are linked to risk of haematological malignancies and cardiovascular disease. Recent observations suggest that smaller clones (VAF<2%) are also associated with adverse outcomes. Our aims were to determine the prevalence of clonal haematopoiesis driven by clones of variable sizes in individuals with obesity treated by usual care or bariatric surgery (a treatment that improves metabolic status), and to examine the expansion of clones in relation to age and metabolic dysregulation over up to 20 years.
Methods: Clonal haematopoiesis-driver mutations (CHDMs) were identified in blood samples from participants of the Swedish Obese Subjects intervention study. Using an ultrasensitive assay, we analysed single-timepoint samples from 1050 individuals treated by usual care and 841 individuals who had undergone bariatric surgery, and multiple-timepoint samples taken over 20 years from a subset (n = 40) of the individuals treated by usual care.
Findings: In this explorative study, prevalence of CHDMs was similar in the single-timepoint usual care and bariatric surgery groups (20.6% and 22.5%, respectively, P = 0.330), with VAF ranging from 0.01% to 31.15%. Clone sizes increased with age in individuals with obesity, but not in those who underwent bariatric surgery. In the multiple-timepoint analysis, VAF increased by on average 7% (range -4% to 24%) per year and rate of clone growth was negatively associated with HDL-cholesterol (R = -0.68, 1.74 E -04 ).
Interpretation: Low HDL-C was associated with growth of haematopoietic clones in individuals with obesity treated by usual care.
Funding: The Swedish Research Council, The Swedish state under an agreement between the Swedish government and the county councils, the ALF (Avtal om Läkarutbildning och Forskning) agreement, The Swedish Heart-Lung Foundation, The Novo Nordisk Foundation, The European Research Council, The Netherlands Organisation for Scientific Research.
Competing Interests: Declaration of interests Dr F.M. Kristensson is supported by a grant from the Swedish State under an agreement between the Swedish government and the county councils, the ALF (Avtal om Läkarutbildning och Forskning) agreement, grant ALFGBG-970993 and has received a travel grant from the Gothenburg Society of Medicine. Ms. M. Steehouwer, Dr C Gilissen, Dr H.G. Brunner, and Dr A. Hoischen are supported by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 779257. Dr C. Gilissen is a member of the board of the European Society of Human Genetics (ESHG) and a member of the scientific programme committee of ESHG. Dr H.G. Brunner is a co-coordinator of the Solve-RD project. Dr M.G. Netea is a scientific founder of and owns stock in Trained Therapeuticx Discovery, has received an unrestricted grant from ViiV HealthCare, and a Spinoza Grant from The Netherlands Organisation for Scientific Research. Dr B. Carlsson is employed by and owns stock in AstraZeneca. Dr L.M.S. Carlsson has received consulting fees from Johnson & Johnson. All other authors declare they have no competing interests.
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