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

Johanna C Andersson-Assarsson¹, Rosanne C van Deuren², Felipe M Kristensson³, Marloes Steehouwer⁴, Kajsa Sjöholm¹, Per-Arne Svensson⁵, Marc Pieterse⁶, Christian Gilissen⁴, Magdalena Taube¹, Peter Jacobson¹, Rosie Perkins¹, Han G Brunner⁷, Mihai G Netea⁸, Markku Peltonen⁹, Björn Carlsson¹⁰, Alexander Hoischen¹¹, Lena M S Carlsson¹²

Affiliations

¹ Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-405 30, Sweden.
² 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.
³ 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.
⁴ 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.
⁵ Institute of Health and Care Sciences, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-405 30, Sweden.
⁶ Department of Human Genetics, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ 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.
¹¹ 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.
¹² 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.

PMID: 37209535
PMCID: PMC10209127
DOI: 10.1016/j.ebiom.2023.104621

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

Johanna C Andersson-Assarsson et al. EBioMedicine. 2023 Jun.

. 2023 Jun:92:104621.

doi: 10.1016/j.ebiom.2023.104621. Epub 2023 May 18.

Authors

Affiliations

¹ Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-405 30, Sweden.
² 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.
³ 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.
⁴ 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.
⁵ Institute of Health and Care Sciences, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-405 30, Sweden.
⁶ Department of Human Genetics, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ 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.
¹¹ 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.
¹² 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.

PMID: 37209535
PMCID: PMC10209127
DOI: 10.1016/j.ebiom.2023.104621

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^-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.

Keywords: Bariatric surgery; Clonal haematopoiesis; Clone size; HDL-Cholesterol; Insulin resistance; Obesity.

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Conflict of interest statement

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.

Figures

**Fig. 1**
**Characteristics of the single- and multiple-timepoint groups. (a)** Sex, age, and BMI distribution in the single-timepoint groups (1050 + 841 individuals). **(b)** Sex distribution and distribution of clinical variables at the indicated follow-up timepoints in the multiple-timepoint usual care group (40 individuals).

**Fig. 2**
**CHDM size in relation to age in the single-timepoint usual care and bariatric surgery groups.** Comparison of the correlation between age and clone size (VAF) in individuals with obesity given usual care (shown in blue) and individuals with obesity that underwent bariatric surgery at least one year prior to DNA sampling (shown in orange).

**Fig. 3**
**Rate of CHDM growth in relation to age and metabolic dysfunction. (a)** VAF in relation to age for the 32 most important trajectories. The average mixed linear model (MLM) regression line and equation is shown in black. All individual MLM regression lines are shown in various colours, in purple the trajectory with maximum slope and accompanying equation, in orange the trajectory with minimum slope and accompanying equation. **(b)** VAFs and slopes for CHDMs in *DNMT3A* [p.(Arg822Cys)] in 4 individuals and *DNMT3A* [p.(Arg882His)] in 2 individuals. **(c)** Heatmap of Spearman R correlations between all individual trajectory effect estimates from our MLM to averaged (based on the three first follow-up timepoints) metabolic clinical parameters. **(d)** Positive Spearman R correlation between individual trajectory effect estimates and insulin. **(e)** Positive Spearman R correlation between individual trajectory effect estimates and HOMA-index. **(f)** Negative Spearman R correlation between individual trajectory effect estimates and HDL-C.

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

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Full Text Sources

Medical