Clonal Hematopoiesis of Indeterminate Potential: an Expanding Genetic Cause of Cardiovascular Disease.
TL;DR: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel cardiovascular risk factor that develops as aging HSCs acquire somatic mutations which confer a clonal survival advantage in their progeny.
Abstract: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel cardiovascular risk factor that develops as aging hematopoietic stem cells (HSCs) acquire somatic mutations which confer a clonal survival advantage in their progeny. These cells confer increased leukemogenic risk but confer a greater absolute risk of cardiovascular disease—which appears to be mediated through altered inflammatory pathways. Here we review the evidence the risk of cardiovascular disease conferred by CHIP. We also review the evidence regarding risk factors associated with CHIP. The most recent evidence suggests that CHIP is associated with increased cardiovascular risk beyond atherosclerosis, which has been established in multiple studies, but also in heart failure and aortic valve stenosis. Additionally, the list of conditions associated with CHIP continues to grow including germline genetics, smoking, cancer therapies, radiation exposure, premature menopause, and unhealthy diet. CHIP is a cardiovascular risk factor of increasingly recognized importance, and new data continues to emerge about the risks it confers, which will need more prospective validation. Although risk factors for CHIP are being identified, relatively little is known about the mechanisms by which CHIP develops, which requires further study.
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TL;DR: In this article , the authors reviewed the relationship of lifestyle and environmental risk factors predisposing to somatic mutations and CHIP and provided an overview on age-related cardiovascular outcomes and found that CHIP has been associated with accelerated atherosclerosis and cardiovascular disease in both epidemiological and experimental studies.
Abstract: Clonal hematopoiesis of indeterminate potential (CHIP) has been identified as a novel cardiovascular risk factor. Here we review the relationship of lifestyle and environmental risk factors predisposing to somatic mutations and CHIP and provide an overview on age-related cardiovascular outcomes.CHIP has been associated with accelerated atherosclerosis and cardiovascular disease in both epidemiological and experimental studies. The most commonly mutated candidate driver genes are DNMT3A, TET2, JAK2, and ASXL1. The underlying mechanisms appear predominantly related to inflammatory pathways. Although age is the dominant risk factor for developing CHIP, emerging evidence suggests that other factors such as smoking, obesity/type 2 diabetes, or an unhealthy diet play a role in the occurrence of somatic mutations. Evidence suggests a strong link between vascular risk factors, somatic hematopoietic mutations, and age-related cardiovascular disease. Further studies on CHIP biology are required to identify targeted interventions for risk reduction in patients with CHIP and inform the utility of screening strategies.
5 citations
TL;DR: Clonal hematopoiesis (CH) as mentioned in this paper is defined as clonal expansion of peripheral blood cells on the basis of somatic mutations, without overt hematological malignancy.
Abstract: Abstract Cardiovascular and oncological diseases represent the global major causes of death. For both, a novel and far-reaching risk factor has been identified: clonal hematopoiesis (CH). CH is defined as clonal expansion of peripheral blood cells on the basis of somatic mutations, without overt hematological malignancy. The most commonly affected genes are TET2 , DNMT3A , ASXL1 and JAK2 . By the age of 70, at least 20–50% of all individuals carry a CH clone, conveying a striking clinical impact by increasing all-cause mortality by 40%. This is due predominantly to a nearly two-fold increase of cardiovascular risk, but also to an elevated risk of malignant transformation. Individuals with CH show not only increased risk for, but also worse outcomes after arteriosclerotic events, such as stroke or myocardial infarction, decompensated heart failure and cardiogenic shock. Elevated cytokine levels, dysfunctional macrophage activity and activation of the inflammasome suggest that a vicious cycle of chronic inflammation and clonal expansion represents the major functional link. Despite the apparently high impact of this entity, awareness, functional understanding and especially clinical implications still require further research. This review provides an overview of the current knowledge of CH and its relation to cardiovascular and hematological diseases. It focuses on the basic functional mechanisms in the interplay between atherosclerosis, inflammation and CH, identifies issues for further research and considers potential clinical implications.
4 citations
Journal Article•
TL;DR: A recent review of liquid biopsies for pediatric oncology can be found in this article , where the authors provide a survey of pediatric cell-free DNA (cfDNA) studies, illustrate their potential applications in pediatric cancer, and discuss technological challenges and approaches to overcome them.
Abstract: Liquid biopsies have emerged as a noninvasive alternative to tissue biopsy with potential applications during all stages of pediatric oncology care. The purpose of this review is to provide a survey of pediatric cell-free DNA (cfDNA) studies, illustrate their potential applications in pediatric oncology, and to discuss technological challenges and approaches to overcome these hurdles.Recent literature has demonstrated liquid biopsies' ability to inform treatment selection at diagnosis, monitor clonal evolution during treatment, sensitively detect minimum residual disease following local control, and provide sensitive posttherapy surveillance. Advantages include reduced procedural anesthesia, molecular profiling unbiased by tissue heterogeneity, and ability to track clonal evolution. Challenges to wider implementation in pediatric oncology, however, include blood volume restrictions and relatively low mutational burden in childhood cancers. Multiomic approaches address challenges presented by low-mutational burden, and novel bioinformatic analyses allow a single assay to yield increasing amounts of information, reducing blood volume requirements.Liquid biopsies hold tremendous promise in pediatric oncology, enabling noninvasive serial surveillance with adaptive care. Already integrated into adult care, recent advances in technologies and bioinformatics have improved applicability to the pediatric cancer landscape.
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Brigham and Women's Hospital1, Novartis2, Baylor College of Medicine3, Federal University of São Paulo4, Technische Universität München5, University of Amsterdam6, St. John's University7, University of Pavol Jozef Šafárik8, McGill University9, First Faculty of Medicine, Charles University in Prague10, University of Szeged11, Iuliu Hațieganu University of Medicine and Pharmacy12, University of East Anglia13, Tohoku University14, Sahlgrenska University Hospital15
TL;DR: Antiinflammatory therapy targeting the interleukin‐1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid‐level lowering.
Abstract: BackgroundExperimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. MethodsWe conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. ResultsAt 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in t...
5,660 citations
Broad Institute1, Harvard University2, Hannover Medical School3, University of Helsinki4, Minerva Foundation Institute for Medical Research5, University of Southern California6, National Institutes of Health7, National Institute for Health and Welfare8, University of Mississippi Medical Center9, University of Mississippi10, Massachusetts Institute of Technology11, University of Michigan12, University of Oxford13, King Abdulaziz University14, Danube University Krems15, Albert Einstein College of Medicine16
TL;DR: Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease.
Abstract: Background The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. Methods We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. Results Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). Conclusions Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.)
3,183 citations
TL;DR: Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death.
Abstract: Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent. Methods We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling. Results Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow–biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones. Conclusions Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers. (Funded by the National Human Genome Research Institute and others.)
2,497 citations
Brigham and Women's Hospital1, Massachusetts Institute of Technology2, Harvard University3, Lund University4, Icahn School of Medicine at Mount Sinai5, Mayo Clinic6, British Heart Foundation7, Centro Nacional de Investigaciones Cardiovasculares8, University of Cambridge9, Wellcome Trust10, University of Pennsylvania11
TL;DR: The presence of CHIP in peripheral‐blood cells was associated with nearly a doubling in the risk of coronary heart disease in humans and with accelerated atherosclerosis in mice.
Abstract: BackgroundClonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear. MethodsWe used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells and associated such presence with coronary heart disease using samples from four case–control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls. To assess causality, we perturbed the function of Tet2, the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice. ResultsIn nested case–control analyses from two prospective cohorts, carriers of CHIP had a risk of c...
1,536 citations
TL;DR: Among patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower risk of ischemic cardiovascular events than placebo.
Abstract: Background Experimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medi...
1,426 citations