20 年来，与年龄相关的突变驱动的克隆性造血的演变与肥胖中的代谢功能障碍有关。
Evolution of age-related mutation-driven clonal haematopoiesis over 20 years is associated with metabolic dysfunction in obesity.
机构信息
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.
出版信息
EBioMedicine. 2023 Jun;92:104621. doi: 10.1016/j.ebiom.2023.104621. Epub 2023 May 18.
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.
背景
体细胞突变导致的血液克隆，其等位基因变异频率（VAF）≥2%，随年龄增长而增加，并与血液系统恶性肿瘤和心血管疾病的风险相关。最近的观察结果表明，较小的克隆（VAF<2%）也与不良预后相关。我们的目的是确定在接受常规治疗或减肥手术（改善代谢状态的治疗方法）治疗的肥胖个体中，不同大小克隆驱动的克隆性造血的流行程度，并检查在长达 20 年的时间内，克隆的扩展与年龄和代谢失调的关系。
方法
在瑞典肥胖受试者干预研究的参与者的血液样本中鉴定了克隆性造血驱动突变（CHDM）。使用超灵敏检测方法，我们分析了来自 1050 名接受常规治疗和 841 名接受减肥手术的个体的单次样本，以及来自接受常规治疗的个体子集（n=40）在 20 多年时间内采集的多次样本。
结果
在这项探索性研究中，单次常规治疗和减肥手术组的 CHDM 患病率相似（分别为 20.6%和 22.5%，P=0.330），VAF 范围为 0.01%至 31.15%。在肥胖个体中，随着年龄的增长，克隆大小增加，但在接受减肥手术的个体中没有增加。在多次时间点分析中，VAF 平均每年增加 7%（范围为-4%至 24%），克隆生长速度与高密度脂蛋白胆固醇（HDL-C）呈负相关（R=-0.68，1.74E）。
解释
在接受常规治疗的肥胖个体中，低 HDL-C 与造血克隆的生长相关。
资金
瑞典研究委员会、瑞典政府与县议会之间的协议下的瑞典国家、ALF（医师培训与研究协议）、瑞典心脏肺基金会、诺和诺德基金会、欧洲研究委员会、荷兰科学研究组织。
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