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

Humans Young Adult Adult Clonal Hematopoiesis / genetics Obesity / genetics Bariatric Surgery / adverse effects Mutation Cardiovascular Diseases / etiology
Bariatric surgery Clonal haematopoiesis Clone size HDL-Cholesterol Insulin resistance Obesity

Journal

EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039

Informations de publication

Date de publication:
Jun 2023
Historique:
received: 14 12 2022
revised: 02 05 2023
accepted: 03 05 2023
medline: 19 6 2023
pubmed: 21 5 2023
entrez: 20 5 2023
Statut: ppublish

Résumé

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. 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. 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 Low HDL-C was associated with growth of haematopoietic clones in individuals with obesity treated by usual care. 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.

Sections du résumé

BACKGROUND 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 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 RESULTS
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 CONCLUSIONS
Low HDL-C was associated with growth of haematopoietic clones in individuals with obesity treated by usual care.
FUNDING BACKGROUND
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.

Identifiants

DOI: 10.1016/j.ebiom.2023.104621 PMID: 37209535 PMC: PMC10209127
pubmed: 37209535
pii: S2352-3964(23)00186-X
doi: 10.1016/j.ebiom.2023.104621
pmc: PMC10209127
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

104621

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

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.

Auteurs

Johanna C Andersson-Assarsson (JC)

Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-405 30, Sweden.

Rosanne C van Deuren (RC)

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.

Felipe M Kristensson (FM)

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.

Marloes Steehouwer (M)

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.

Kajsa Sjöholm (K)

Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-405 30, Sweden.

Per-Arne Svensson (PA)

Institute of Health and Care Sciences, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-405 30, Sweden.

Marc Pieterse (M)

Department of Human Genetics, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.

Christian Gilissen (C)

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.

Magdalena Taube (M)

Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-405 30, Sweden.

Peter Jacobson (P)

Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-405 30, Sweden.

Rosie Perkins (R)

Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-405 30, Sweden.

Han G Brunner (HG)

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.

Mihai G Netea (MG)

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.

Markku Peltonen (M)

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.

Björn Carlsson (B)

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.

Alexander Hoischen (A)

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: alexander.hoischen@radboudumc.nl.

Lena M S Carlsson (LMS)

Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-405 30, Sweden. Electronic address: lena.carlsson@medic.gu.se.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Evolution of age-related mutation-driven...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Jeune adulte › Evolution of age-related mutation-driven...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Evolution of age-related mutation-driven...
questionsmedicales.fr › Phénomènes physiologiques respiratoires et circulatoires › Phénomènes physiogiques du sang › Hématopoïèse › Hématopoïèse clonale › Evolution of age-related mutation-driven...
questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Obésité › Evolution of age-related mutation-driven...
questionsmedicales.fr › Procédures de chirurgie opératoire › Chirurgie bariatrique › Evolution of age-related mutation-driven...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Evolution of age-related mutation-driven...
questionsmedicales.fr › Maladies cardiovasculaires › Evolution of age-related mutation-driven...