Evolution of age-related mutation-driven clonal haematopoiesis over 20 years is associated with metabolic dysfunction in obesity.

Magdalena Taube, Lena M S Carlsson, Alexander Hoischen, Björn Carlsson, Markku Peltonen, Mihai G Netea, Han G Brunner, Rosie Perkins, Peter Jacobson, Johanna C Andersson-Assarsson, Christian Gilissen, Marc Pieterse, Per-Arne Svensson, Kajsa Sjöholm, Marloes Steehouwer, Felipe M Kristensson, Rosanne C van Deuren

Journal: EBioMedicine 2023;92():104621

PMID: 37209535

Free Full Text on Elsevier Science View on PubMed

Abstract

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).

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.

Address: Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-405 30, Sweden.; Department of Human Genetics, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands; Radboud Expertise Center for Immunodeficiency and Autoinflammation and Radboud Center for Infectious Disease (RCI), Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-405 30, Sweden; Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, SE-413 45, Sweden.; Department of Human Genetics, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.; Institute of Health and Care Sciences, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-405 30, Sweden.; Department of Human Genetics, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.; Department of Human Genetics, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, 6200 MD, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands; GROW School of Oncology and Developmental Biology, and MHeNs School of Mental Health and Neuroscience, Maastricht University, Maastricht, 6500 MD, the Netherlands.; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands; Radboud Expertise Center for Immunodeficiency and Autoinflammation and Radboud Center for Infectious Disease (RCI), Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands; Department of Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, 53115, Germany.; Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, SE-141 83, Sweden; Public Health Promotion Unit, National Institute for Health and Welfare, Helsinki, 00271, Finland.; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-405 30, Sweden; Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, SE-431 83, Sweden.; Department of Human Genetics, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands; Radboud Expertise Center for Immunodeficiency and Autoinflammation and Radboud Center for Infectious Disease (RCI), Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands. Electronic address: [email protected].; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-405 30, Sweden. Electronic address: [email protected].

DOI: 10.1016/j.ebiom.2023.104621

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MeSH Terms: Humans, Young Adult, Adult, Clonal Hematopoiesis, Obesity, Bariatric Surgery, Mutation, Cardiovascular Diseases