Distribution of clonal hematopoiesis of indeterminate potential (CHIP) is not associated with race in patients with plasma cell neoplasms.
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ABSTRACT:
SUBMITTER: Gagnon MF
PROVIDER: S-EPMC9325693 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Clonal hematopoiesis of indeterminate potential (CHIP) is the presence of a clonally expanded hematopoietic stem cell caused by a leukemogenic mutation in individuals without evidence of hematologic malignancy, dysplasia, or cytopenia. CHIP is associated with a 0.5-1.0% risk per year of leukemia. Remarkably, it confers a two-fold increase in cardiovascular risk independent of traditional risk factors. Roughly 80% of patients with CHIP have mutations in epigenetic regulators DNMT3A, TET2, ASXL1, DNA damage repair genes PPM1D, TP53, the regulatory tyrosine kinase JAK2, or mRNA spliceosome components SF3B1, and SRSF2. CHIP is associated with a pro-inflammatory state that has been linked to coronary artery disease, myocardial infarction, and venous thromboembolic disease, as well as prognosis among those with aortic stenosis and heart failure. Heritable and acquired risk factors are associated with increased CHIP prevalence, including germline variation, age, unhealthy lifestyle behaviors (i.e. smoking, obesity), inflammatory conditions, premature menopause, HIV and exposure to cancer therapies. This review aims to summarize emerging research on CHIP, the mechanisms underlying its important role in propagating inflammation and accelerating cardiovascular disease, and new studies detailing the role of associated risk factors and co-morbidities that increase CHIP prevalence.
| S-EPMC8629838 | biostudies-literature
Project description:BackgroundCardiovascular diseases (CVDs) are the leading cause of mortality in India. Residual risk exists in patients receiving optimal guideline-directed medical therapy. Possession of certain somatic mutations, at a variant allele frequency of ≥ 2% in peripheral blood, driving clonal expansion in the absence of cytopenias and dysplastic hematopoiesis is defined as clonal hematopoiesis of indeterminate potential (CHIP). Recently, it was found that carriers of CHIP had a higher risk to have coronary artery disease (CAD) and early-onset myocardial infarction. Association of CHIP with heart failure and valvular heart diseases is increasingly being considered. The common link that connects CHIP mutations and CVDs is inflammation leading to increased expression of cytokines and chemokines. We intended to do a systematic review about the association of CHIP mutations and CVD along with identifying specific CHIP mutations involved in increasing the risk of having CVDs. We performed an extensive literature search in PubMed and Google Scholar databases. Out of 302 articles, we narrowed it down to 10 studies based on our pre-specified criteria. The methodology adopted for the identification of CHIP mutations in the selected studies included - whole-exome sequencing (n = 3), whole-genome analysis (n = 1), transcriptome profiling analysis (n = 1), whole-genome analysis (n = 1), and single-cell RNA-sequencing (n = 1). We found that the available literature suggested an association between CHIP and CVD. The most commonly described CHIP mutations in patients with CVD are DNMT3A, TET2, ASXL1, TP53, JAK2, and SF3B. We further analyzed the commonly mutated CHIP genes using bioinformatics tools. Protein function and interaction analysis were performed using the g: Profiler and GeneMANIA online tools. The results revealed significant bio grid interactions for molecular functions, biological processes, and biological pathways. Interaction analysis showed significant physical and co-expression interactions.Short conclusionWe conclude that there exists a significant association between CHIP mutations and CVD with DNMT3A, TET2, ASXL1, TP53, JAK2, and SF3B as the commonly implicated genes. The recognition of the link between CHIP and cardiovascular events will expand our understanding of residual risk and will open up new avenues of investigation and therapeutic modalities in the management of patients with CVD.
| S-EPMC8287286 | biostudies-literature
Project description:Clonally restricted hematopoiesis is a common aging-associated biological state that predisposes to subsequent development of a hematological malignancy or cardiovascular death. Clonal expansion driven by leukemia-associated somatic mutations, such as DNMT3A, ASXL1, or TET2, is best characterized, but oligoclonality can also emerge without recognized leukemia-driver mutations, perhaps as a result of stochastic neutral drift. Murine models provide compelling evidence that a major mechanism of increased cardiovascular mortality in the context of clonal hematopoiesis is accelerated atherogenesis driven by inflammasome-mediated endothelial injury, resulting from proinflammatory interactions between endothelium and macrophages derived from circulating clonal monocytes. Altered inflammation likely influences other biological processes as well. The rate of development of overt neoplasia in patients with clonal hematopoiesis of indeterminate potential (CHIP), as currently defined, is 0.5% to 1% per year. Contributing factors to clonal progression other than acquisition of secondary mutations in hematopoietic cells (ie, stronger leukemia drivers) are incompletely understood. Disordered endogenous immunity in the context of increased proliferative pressure, short telomeres leading to chromosomal instability, an unhealthy marrow microenvironment that favors expansion of clonal stem cells and acquisition of new mutations while failing to support healthy hematopoiesis, and aging-associated changes in hematopoietic stem cells, including altered DNA damage response, an altered transcriptional program, and consequences of epigenetic alterations, are all potential contributors to clonal progression. Clinical management of patients with CHIP includes monitoring for hematological changes and reduction of modifiable cardiovascular risk factors; eventually, it will also likely include anti-inflammatory therapies and targeted approaches to prune emergent dangerous clones.
| S-EPMC6258914 | biostudies-other
Project description:Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown and to date no genetic mechanisms for AKI have been established. Clonal hematopoiesis of indeterminate potential (CHIP) is a recently recognized biological mechanism conferring risk of several chronic aging diseases including cardiovascular disease, pulmonary disease and liver disease. In CHIP, blood stem cells acquire mutations in myeloid cancer driver genes such as DNMT3A, TET2, ASXL1 and JAK2 and the myeloid progeny of these mutated cells contribute to end-organ damage through inflammatory dysregulation. We sought to establish whether CHIP causes acute kidney injury (AKI). To address this question, we first evaluated associations with incident AKI events in three population-based epidemiology cohorts (N = 442,153). We found that CHIP was associated with a greater risk of AKI (adjusted HR 1.26, 95% CI: 1.19-1.34, p<0.0001), which was more pronounced in patients with AKI requiring dialysis (adjusted HR 1.65, 95% CI: 1.24-2.20, p=0.001). The risk was particularly high in the subset of individuals where CHIP was driven by mutations in genes other than DNMT3A (HR: 1.49, 95% CI: 1.37-1.61, p<0.0001). We then examined the association between CHIP and recovery from AKI in the ASSESS-AKI cohort and identified that non-DNMT3A CHIP was more common among those with a non-resolving pattern of injury (HR 2.3, 95% CI: 1.14-4.64, p = 0.03). To gain mechanistic insight, we evaluated the role of Tet2-CHIP to AKI in ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) mouse models. In both models, we observed more severe AKI and greater post-AKI kidney fibrosis in Tet2-CHIP mice. Kidney macrophage infiltration was markedly increased in Tet2-CHIP mice and Tet2-CHIP mutant renal macrophages displayed greater proinflammatory responses. In summary, this work establishes CHIP as a genetic mechanism conferring risk of AKI and impaired kidney function recovery following AKI via an aberrant inflammatory response in CHIP derived renal macrophages.
| S-EPMC10246021 | biostudies-literature
Project description:Clonal hematopoiesis of indeterminate potential (CHIP) is predictive of hematological cancers and cardiovascular diseases, but the etiology of CHIP initiation and clonal expansion is unknown. Several lines of evidence suggest that proinflammatory cytokines may favor mutated hematopoietic stem cell expansion. To investigate the potential link between inflammation and CHIP, we performed targeted deep sequencing of 11 genes previously implicated in CHIP in 1887 subjects aged >70 years from the Montreal Heart Institute Biobank, of which 1359 had prior coronary artery disease (CAD), and 528 controls did not. We assessed association of CHIP with log transformed high-sensitivity C-reactive protein (hs-CRP), a validated biomarker of inflammation. CHIP was identified in 427 of the 1887 subjects (22.6%). CHIP mutations were more frequently identified in DNMT3A (11.6%) and TET2 (6.1%), with a higher proportion of TET2 mutations occurring in controls than in patients with CAD (9.0% vs 4.9%, P < .001). CHIP carriers had 21% higher hs-CRP levels compared with their noncarrier counterparts (e? = 1.21, 95% confidence interval [CI]: 1.08 to 1.36; P = .001). A similar effect was observed in the subgroup of patients with known CAD (e? = 1.22, 95% CI: 1.06 to 1.41; P = .005). These findings confirm the association between inflammation and CHIP. This association may open investigational avenues aimed at documenting mechanisms linking inflammation to clonal progression and ultimately supports prevention interventions to attenuate CHIP's impact on cardiovascular disease and cancer.
| S-EPMC7284088 | biostudies-literature
Project description:Recent studies have revealed that clonal hematopoiesis of indeterminate potential (CHIP) is an important risk factor for therapy-related myeloid neoplasms (t-MNs). CHIP is currently defined as a clonal hematopoietic population carrying somatic point mutations in 1 of the leukemia-associated genes. Patients with t-MNs often present with chromosomal abnormalities in addition to somatic point mutations. It remains unclear whether chromosomal abnormalities can cooccur with point mutations as part of CHIP. Here we report that 3 of 14 patients with t-MNs had low amplitude but detectable chromosome arm-level copy number alterations (CNAs) in the peripheral blood samples that were taken at the time of their primary cancer diagnosis and before exposure to therapy. These CNAs were the same CNAs seen in t-MN bone marrow samples and affected the same allele, suggesting the same clonal origin. These data suggest that not only somatic point mutations but also chromosome arm-level CNAs are detectable as CHIP and preexist before patients' exposure to chemotherapy and/or radiation therapy. These data suggest that screening of both somatic point mutations and CNAs might allow more complete ascertainment of CHIP.
| S-EPMC5728325 | biostudies-literature
Project description:The present study aimed to gain insights into the pathological process of Calcific Aortic Valve Disease (CAVD) in CHIP carriers. To this end, we screened for CHIP, by DNA sequencing of blood samples, a cohort of 168 patients with calcified aortic stenosis who had undergone valve replacement via transcatheter aortic valve implantation (TAVI) or surgically.
2022-08-02 | E-MTAB-11352 | biostudies-arrayexpress
Project description:BACKGROUND:Clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations increase the risk of atherosclerotic heart disease. Comorbidities significantly impact the prognosis of patients with myelodysplastic syndromes (MDS). The objective of this study was to determine the association and impact of CHIP mutations with comorbidities in patients with MDS. METHODS:This retrospective analysis of 566 consecutive patients with MDS was conducted at The University of Texas MD Anderson Cancer Center from August 2013 to December 2016. The 27-item Adult Comorbidity Evaluation (ACE-27) scale was used to assess the severity of comorbid conditions. Next-generation sequencing was used to detect the presence of CHIP mutations in bone marrow aspirates. Spearman correlations and logistic regression analyses were used to determine the association between mutations and comorbidities. RESULTS:Mutations in the genes tet methylcytosine dioxygenase 2 (TET2), ASXL transcriptional regulator 1 (ASXL1), DNA methyltransferase 3? (DNMT3A), Janus kinase 2 (JAK2), and tumor protein 53 (TP53) were noted in 20%, 18%, 9%, 2%, and 21% of patients, respectively. Patients with DNMT3A and JAK2 mutations had higher likelihoods of a prior history of myocardial infarction (odds ratio, 2.62; P = .03) and veno-occlusive disease (odds ratio, 6.48; P = .02), respectively. TP53 mutation was associated with a prior history of malignancy. Patients with TET2 mutation had no association with any comorbidity. A prognostic model including the revised International Prognostic Scoring System classification, the ACE-27 score, and TP53 mutation status (the I-RAT model) predicted median overall survival. CONCLUSIONS:In patients with MDS, the presence of CHIP-associated mutations is associated with comorbidities. DNMT3A and JAK2 mutations were associated with higher likelihoods of prior myocardial infarction and thrombotic events. There was no association between comorbidity and TET2 mutation. Incorporating the revised International Prognostic Scoring System classification with the ACE-27 and TP53 mutation status improved outcome prediction in patients with MDS.
| S-EPMC6742577 | biostudies-literature
Project description:People living with human immunodeficiency virus (PLWH) have significantly increased risk for cardiovascular disease in part due to inflammation and immune dysregulation. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition and expansion of hematopoietic stem cells due to leukemogenic driver mutations, increases risk for both hematologic malignancy and coronary artery disease (CAD). Since increased inflammation is hypothesized to be both a cause and consequence of CHIP, we hypothesized that PLWH have a greater prevalence of CHIP. We searched for CHIP in multi-ethnic cases from the Swiss HIV Cohort Study (SHCS, n = 600) and controls from the Atherosclerosis Risk in the Communities study (ARIC, n = 8111) from blood DNA-derived exome sequences. We observed that HIV is associated with a twofold increase in CHIP prevalence, both in the whole study population and in a subset of 230 cases and 1002 matched controls selected by propensity matching to control for demographic imbalances (SHCS 7%, ARIC 3%, p = 0.005). We also observed that ASXL1 is the most commonly mutated CHIP-associated gene in PLWH. Our results suggest that CHIP may contribute to the excess cardiovascular risk observed in PLWH.
| S-EPMC8755790 | biostudies-literature
Project description: Not available
| S-EPMC5981171 | biostudies-literature