Interplay between genetics and epigenetics in modulating the risk of venous thromboembolism: A new challenge for personalized therapy

Benincasa, Giuditta; Costa, Dário Alves da Silva; Infante, Teresa; Lucchese, Roberta; Donatelli, Francesco; Napoli, Claudio

doi:10.1016/j.thromres.2019.03.008

Cited by 30 publications

(29 citation statements)

References 73 publications

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“…Independent of therapy choice, identifying patients at greatest risk for recurrent VTE, who might benefit from long-term secondary TA B L E 1 Some research priorities in venous thromboembolism across the spectrum of translational research Other avenues to pursue include genetic screening, which is complicated by epigenetic factors that also contribute to disease. 16 Unbiased "omics" approaches that measure circulating microRNAs has identified candidates that are associated with VTE recurrence. 17 Metabolic screening has also shown potential to identify new biomarkers that influence VTE.…”

Section: T1 -Translational Research: From Animals To Humansmentioning

confidence: 99%

Venous thromboembolism research priorities: A scientific statement from the American Heart Association and the International Society on Thrombosis and Haemostasis

Cushman

Barnes

Creager

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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Venous thromboembolism (VTE) is a major cause of morbidity and mortality. The impact of the Surgeon General's Call to Action in 2008 has been lower than expected given the public health impact of this disease. This scientific statement highlights future research priorities in VTE, developed by experts and a crowdsourcing survey across 16 scientific organizations. At the fundamental research level (T0), researchers need to identify pathobiologic causative mechanisms for the 50% of patients with unprovoked VTE and better understand mechanisms that differentiate hemostasis from thrombosis. At the human level (T1), new methods for diagnosing, treating, and preventing VTE will allow tailoring of diagnostic and therapeutic approaches to individuals. At the patient level (T2), research efforts are required to understand how foundational evidence impacts care of patients (eg, biomarkers). New treatments, such as catheter-based therapies, require further testing to identify which patients are most likely to experience benefit. At the practice level (T3), translating evidence into practice remains challenging. Areas of overuse and underuse will require evidence-based tools to improve care delivery. At the community and population level (T4), public awareness campaigns need thorough impact assessment. Large population-based cohort studies can elucidate the biologic and environmental underpinings of VTE and its complications. To achieve these goals, funding agencies and training

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Section: T1 -Translational Research: From Animals To Humansmentioning

confidence: 99%

Venous thromboembolism research priorities: A scientific statement from the American Heart Association and the International Society on Thrombosis and Haemostasis

Cushman

Barnes

Creager

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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“…Neutrophil extracellular traps (NETs) are circulating double strand DNA (dsDNA)-based complexes which form fibrous structures with histones and granule proteins to trap microorganisms and kills them by antimicrobial properties. 67 On inflammatory stimuli, the overexpression of peptidyl arginine deiminase 4 enzyme can lead to modification of specific arginine into citrulline residues (citrullination) at the level of H3 and H4 tails inducing the expulsion of NETs from activated neutrophils. 67 This process, called NETosis, plays a key role in increasing the risk of venous thromboembolism, owing to the strong capability of circulating histones to enhance generation of thrombin, secretion of Weibel-Palade body and adhesion of platelet and leucocytes.…”

Section: Modified Histonesmentioning

confidence: 99%

“…67 On inflammatory stimuli, the overexpression of peptidyl arginine deiminase 4 enzyme can lead to modification of specific arginine into citrulline residues (citrullination) at the level of H3 and H4 tails inducing the expulsion of NETs from activated neutrophils. 67 This process, called NETosis, plays a key role in increasing the risk of venous thromboembolism, owing to the strong capability of circulating histones to enhance generation of thrombin, secretion of Weibel-Palade body and adhesion of platelet and leucocytes. 67 A prospective cohort study reported that levels of circulating histones incorporated into NETs significantly increased in congenital cardiac patients with adverse events immediately after cardiopulmonary bypass (CPB) with respect to controls.…”

Section: Modified Histonesmentioning

confidence: 99%

“…67 This process, called NETosis, plays a key role in increasing the risk of venous thromboembolism, owing to the strong capability of circulating histones to enhance generation of thrombin, secretion of Weibel-Palade body and adhesion of platelet and leucocytes. 67 A prospective cohort study reported that levels of circulating histones incorporated into NETs significantly increased in congenital cardiac patients with adverse events immediately after cardiopulmonary bypass (CPB) with respect to controls. 68 Importantly, circulating histones reached the maximum value earlier than N-terminal probrain natriuretic peptide, procalcitonin and C reactive protein (CRP) after CPB, suggesting a useful prognostic indicator of adverse events after cardiac surgery.…”

Section: Modified Histonesmentioning

confidence: 99%

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Fluid-based assays and precision medicine of cardiovascular diseases: the ‘hope’ for Pandora’s box?

2019

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Progresses in liquid-based assays may provide novel useful non-invasive indicators of cardiovascular (CV) diseases. By analysing circulating cells or their products in blood, saliva and urine samples, we can investigate molecular changes present at specific time points in each patient allowing sequential monitoring of disease evolution. For example, an increased number of circulating endothelial cells may be a diagnostic biomarker for diabetic nephropathy and heart failure with preserved ejection fraction. The assessment of circulating cell-free DNA (cfDNA) levels may be useful to predict severity of acute myocardial infarction, as well as diagnose heart graft rejection. Remarkably, circulating epigenetic biomarkers, including DNA methylation, histone modifications and non-coding RNAs are key pathogenic determinants of CV diseases representing putative useful biomarkers and drug targets. For example, the unmethylated FAM101A gene may specifically trace cfDNA derived from cardiomyocyte death providing a powerful diagnostic biomarker of apoptosis during ischaemia. Moreover, changes in plasma levels of circulating miR-92 may predict acute coronary syndrome onset in patients with diabetes. Now, network medicine provides a framework to analyse a huge amount of big data by describing a CV disease as a result of a chain of molecular perturbations rather than a single defect (reductionism). We outline advantages and challenges of liquid biopsy with respect to traditional tissue biopsy and summarise the main completed and ongoing clinical trials in CV diseases. Furthermore, we discuss the importance of combining fluid-based assays, big data and network medicine to improve precision medicine and personalised therapy in this field.

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“…5 7 The major epigenetic mechanisms are DNA methylation, histone and non-histone modifications, and non-codingRNA molecules, mainly microRNA (miRNAs) which control gene expression without altering DNA sequence in several cardiovascular diseases. [8][9][10][11][12][13] Remarkably, advanced next-generation sequencing (NGS) platforms emphasised the putative useful role of liquid-based assays for detecting cell-free DNA (cfDNA) and miRNAs to improve precision medicine of HF. 11 14 15 We briefly summarise genetic determinants involved in DCM diagnosis and progression of HF (figure 1).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic-sensitive liquid biomarkers and personalised therapy in advanced heart failure: a focus on cell-free DNA and microRNAs

et al. 2020

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Dilated cardiomyopathy (DCM) represents a common genetic cause of mechanical and/or electrical dysfunction leading to heart failure (HF) onset for which truncating variants in titin (TTN) gene result in the most frequent mutations. Moreover, myocyte and endothelial cell apoptosis is a key endophenotype underlying cardiac remodelling. Therefore, a deeper knowledge about molecular networks leading to acute injury and apoptosis may reveal novel circulating biomarkers useful to better discriminate HF phenotypes, patients at risk of heart transplant as well as graft reject in order to improve personalised therapy. Remarkably, increased plasma levels of cell-free DNA (cfDNA) may reflect the extent of cellular damage, whereas circulating mitochondrial DNA (mtDNA) may be a promising biomarker of poor prognosis in patients with HF. Furthermore, some panels of circulating miRNAs may improve the stratification of natural history of disease. For example, a combination of miR-558, miR-122* and miR-520d-5p, as well as miR-125a-5p, miR-550a-5p, miR-638 and miR-190a, may aid to discriminate different phenotypes of HF ranging from preserved to reduced ejection fraction. We give update on the most relevant genetic determinants involved in DCM and discuss the putative role of non-invasive biomarkers to overcome current limitations of the reductionist approach in HF management.

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Interplay between genetics and epigenetics in modulating the risk of venous thromboembolism: A new challenge for personalized therapy

Cited by 30 publications

References 73 publications

Venous thromboembolism research priorities: A scientific statement from the American Heart Association and the International Society on Thrombosis and Haemostasis

Venous thromboembolism research priorities: A scientific statement from the American Heart Association and the International Society on Thrombosis and Haemostasis

Fluid-based assays and precision medicine of cardiovascular diseases: the ‘hope’ for Pandora’s box?

Epigenetic-sensitive liquid biomarkers and personalised therapy in advanced heart failure: a focus on cell-free DNA and microRNAs

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