Cardiovascular disease (CVD) is the leading cause of death worldwide and considered one of the most environmentally driven diseases. The role of DNA methylation in response to the individual exposure ...for the development and progression of CVD is still poorly understood and a synthesis of the evidence is lacking.
A systematic review of articles examining measurements of DNA cytosine methylation in CVD was conducted in accordance with PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. The search yielded 5,563 articles from PubMed and CENTRAL databases. From 99 studies with a total of 87,827 individuals eligible for analysis, a database was created combining all CpG-, gene- and study-related information. It contains 74,580 unique CpG sites, of which 1452 CpG sites were mentioned in ≥ 2, and 441 CpG sites in ≥ 3 publications. Two sites were referenced in ≥ 6 publications: cg01656216 (near ZNF438) related to vascular disease and epigenetic age, and cg03636183 (near F2RL3) related to coronary heart disease, myocardial infarction, smoking and air pollution. Of 19,127 mapped genes, 5,807 were reported in ≥ 2 studies. Most frequently reported were TEAD1 (TEA Domain Transcription Factor 1) and PTPRN2 (Protein Tyrosine Phosphatase Receptor Type N2) in association with outcomes ranging from vascular to cardiac disease. Gene set enrichment analysis of 4,532 overlapping genes revealed enrichment for Gene Ontology molecular function "DNA-binding transcription activator activity" (q = 1.65 × 10
) and biological processes "skeletal system development" (q = 1.89 × 10
). Gene enrichment demonstrated that general CVD-related terms are shared, while "heart" and "vasculature" specific genes have more disease-specific terms as PR interval for "heart" or platelet distribution width for "vasculature." STRING analysis revealed significant protein-protein interactions between the products of the differentially methylated genes (p = 0.003) suggesting that dysregulation of the protein interaction network could contribute to CVD. Overlaps with curated gene sets from the Molecular Signatures Database showed enrichment of genes in hemostasis (p = 2.9 × 10
) and atherosclerosis (p = 4.9 × 10
).
This review highlights the current state of knowledge on significant relationship between DNA methylation and CVD in humans. An open-access database has been compiled of reported CpG methylation sites, genes and pathways that may play an important role in this relationship.
Lipids are important modifiers of protein function, particularly as parts of lipoproteins, which transport lipophilic substances and mediate cellular uptake of circulating lipids. As such, lipids are ...of particular interest as blood biological markers for cardiovascular disease (CVD) as well as for conditions linked to CVD such as atherosclerosis, diabetes mellitus, obesity and dietary states. Notably, lipid research is particularly well developed in the context of CVD because of the relevance and multiple causes and risk factors of CVD. The advent of methods for high-throughput screening of biological molecules has recently resulted in the generation of lipidomic profiles that allow monitoring of lipid compositions in biological samples in an untargeted manner. These and other earlier advances in biomedical research have shaped the knowledge we have about lipids in CVD. To evaluate the knowledge acquired on the multiple biological functions of lipids in CVD and the trends in their research, we collected a dataset of references from the PubMed database of biomedical literature focused on plasma lipids and CVD in human and mouse. Using annotations from these records, we were able to categorize significant associations between lipids and particular types of research approaches, distinguish non-biological lipids used as markers, identify differential research between human and mouse models, and detect the increasingly mechanistic nature of the results in this field. Using known associations between lipids and proteins that metabolize or transport them, we constructed a comprehensive lipid-protein network, which we used to highlight proteins strongly connected to lipids found in the CVD-lipid literature. Our approach points to a series of proteins for which lipid-focused research would bring insights into CVD, including Prostaglandin G/H synthase 2 (PTGS2, a.k.a. COX2) and Acylglycerol kinase (AGK). In this review, we summarize our findings, putting them in a historical perspective of the evolution of lipid research in CVD.
BACKGROUND
Although polypharmacy is associated with a negative clinical outcome in various settings and commonly observed in patients receiving oral anticoagulation therapy, evidence on the relevance ...for the clinical outcome of anticoagulated patients is currently limited. The aim of the study was to investigate the effect of polypharmacy on the clinical outcomes among patients taking phenprocoumon.
DESIGN
Prospective cohort study.
SETTING
Regular medical care.
PARTICIPANTS
Information on 2011 individuals receiving vitamin K antagonists was available for analysis from the prospective multicenter thrombEVAL study.
MEASUREMENTS
Data were obtained from clinical visits, computer‐assisted interviews, and laboratory measurements. Information on clinical outcome was obtained during a 3‐year follow‐up period and subsequently validated via medical records.
RESULTS
The prevalence of polypharmacy (five drugs or more) was 84.1% (n = 1691). Quality of anticoagulation therapy assessed by time in therapeutic range was lower in individuals on five to eight drugs and nine drugs or more (70.7% and 64.7%, respectively) compared with subjects without polypharmacy (73.4%). In addition, a significantly higher variability of international normalized ratio measurements was found in the presence of polypharmacy. The cumulative incidence of bleeding, hospitalization, and all‐cause mortality, but not for thromboembolic events, increased across groups of medication. In adjusted Cox regression analysis, polypharmacy is an independent risk factor for bleeding (hazard ratio HR≥ 9 drugs vs 1‐4 drugs = 1.62; 95% confidence interval CI = 1.04‐2.52; p = .033); hospitalization (HR≥ 9 drugs vs 1‐4 drugs = 1.60; 95% CI = 1.26‐2.03; p < .001; and all‐cause mortality (HR≥ 9 drugs vs 1‐4 drugs = 2.16; 95% CI = 1.43‐3.27; p < .001) in a dose‐dependent relationship. Per additional drug, bleeding risk was increased by 4%.
CONCLUSIONS
Polypharmacy influences the quality of anticoagulation therapy and translates into an elevated risk of adverse events in anticoagulated patients. This suggests that additional medication intake in such patients should be critically reviewed by physicians, and it highlights the importance of initiating investigations aimed at reducing multiple medication intake. J Am Geriatr Soc 67:463–470, 2019.
Targeted proteomics utilizing antibody-based proximity extension assays provides sensitive and highly specific quantifications of plasma protein levels. Multivariate analysis of this data is hampered ...by frequent missing values (random or left censored), calling for imputation approaches. While appropriate missing-value imputation methods exist, benchmarks of their performance in targeted proteomics data are lacking. Here, we assessed the performance of two methods for imputation of values missing completely at random, the previously top-benchmarked 'missForest' and the recently published 'GSimp' method. Evaluation was accomplished by comparing imputed with remeasured relative concentrations of 91 inflammation related circulating proteins in 86 samples from a cohort of 645 patients with venous thromboembolism. The median Pearson correlation between imputed and remeasured protein expression values was 69.0% for missForest and 71.6% for GSimp (p = 5.8e-4). Imputation with missForest resulted in stronger reduction of variance compared to GSimp (median relative variance of 25.3% vs. 68.6%, p = 2.4e-16) and undesired larger bias in downstream analyses. Irrespective of the imputation method used, the 91 imputed proteins revealed large variations in imputation accuracy, driven by differences in signal to noise ratio and information overlap between proteins. In summary, GSimp outperformed missForest, while both methods show good overall imputation accuracy with large variations between proteins.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recurrent events frequently occur after venous thromboembolism (VTE) and remain difficult to predict based on established genetic, clinical, and proteomic contributors. The role of circulating ...microRNAs (miRNAs) has yet to be explored in detail.
To identify circulating miRNAs predictive of recurrent VTE or death, and to interpret their mechanistic involvement.
Data from 181 participants of a cohort study of acute VTE and 302 individuals with a history of VTE from a population-based cohort were investigated. Next-generation sequencing was performed on EDTA plasma samples to detect circulating miRNAs. The endpoint of interest was recurrent VTE or death. Penalized regression was applied to identify an outcome-relevant miRNA signature, and results were validated in the population-based cohort. The involvement of miRNAs in coregulatory networks was assessed using principal component analysis, and the associated clinical and molecular phenotypes were investigated. Mechanistic insights were obtained from target gene and pathway enrichment analyses.
A total of 1950 miRNAs were detected across cohorts after postprocessing. In the discovery cohort, 50 miRNAs were associated with recurrent VTE or death (cross-validated C-index, 0.65). A weighted miRNA score predicted outcome over an 8-year follow-up period (HRSD, 2.39; 95% CI, 1.98-2.88; P < .0001). The independent validation cohort validated 20 miRNAs (ORSD for score, 3.47; 95% CI, 2.37-5.07; P < .0001; cross-validated-area under the curve, 0.61). Principal component analysis revealed 5 miRNA networks with distinct relationships to clinical phenotype and outcome. Mapping of target genes indicated regulation via transcription factors and kinases involved in signaling pathways associated with fibrinolysis.
Circulating miRNAs predicted the risk of recurrence or death after VTE over several years, both in the acute and chronic phases.
•The role of circulating microRNAs in predicting outcomes following venous thromboembolism (VTE) is still largely unknown.•MicroRNA sequencing was performed in 2 cohorts, representing acute VTE and history of VTE.•A signature of 20 miRNAs was prognostic for recurrent VTE and death in both cohorts.•Mapping of target genes indicated regulation of fibrinolysis-associated pathways.
Background
The role of platelets in the pathogenesis of venous thromboembolism (VTE) is receiving increasing attention; however, limited information is available on platelet function in the acute ...phase of the disease.
Objective
To characterize platelet function according to VTE phenotypes.
Patients/Methods
In total, 154 subjects (isolated pulmonary embolism iPE, n = 28; isolated deep vein thrombosis iDVT, n = 35; DVT+PE, n = 91) were included. In this study platelet function analyzer (PFA)‐200, light transmission aggregometry (LTA), thrombin generation (TG) in presence (PRP) and absence (PFP) of platelets and platelet flow cytometry were investigated. LASSO regression was used to select clinical and platelet biomarkers that distinguish between VTE phenotypes.
Results
PFA‐200 results did not differ between VTE phenotypes. LTA from DVT+PE subjects showed lowest maximum aggregation after epinephrine and adenosine diphosphate compared to iPE and iDVT. Lower % of PAC‐1‐positive platelets after in‐vitro trigger were present in DVT+PE and iPE compared to iDVT. TG in PRP had lower peak height and velocity in DVT+PE and iPE against iDVT. The results of LASSO regression for the distinction between DVT+PE vs iDVT identified 18 variables (AUC =0.93) of which 72% were platelet biomarkers. For distinction between iPE and iDVT, 10 variables were selected (AUC = 0.96) of which 50% were platelet‐related. Obesity was the only variable weakly discriminating between DVT+PE vs iPE (AUC = 0.66).
Conclusion
This explorative study suggests an important distinction between PE‐related phenotypes and iDVT when considering clinical and platelet function data. Lower platelet‐dependent TG along with reduced platelet reactivity suggest higher platelet degranulation in PE‐dependent phenotypes compared to iDVT.
Animal experiments and early phase human trials suggest that inhibition of factor XIa (FXIa) safely prevents venous thromboembolism (VTE), and specific murine models of sepsis have shown potential ...efficacy in alleviating cytokine storm. These latter findings support the role of FXI beyond coagulation. Here, we combine targeted proteomics, machine learning and bioinformatics, to discover associations between FXI activity (FXI:C) and the plasma protein profile of patients with VTE. FXI:C was measured with a modified activated partial prothrombin time (APTT) clotting time assay. Proximity extension assay-based protein profiling was performed on plasma collected from subjects from the Genotyping and Molecular Phenotyping of Venous Thromboembolism (GMP-VTE) Project, collected during an acute VTE event (n = 549) and 12-months after (n = 187). Among 444 proteins investigated, N = 21 and N = 66 were associated with FXI:C during the acute VTE event and at 12 months follow-up, respectively. Seven proteins were identified as FXI:C-associated at both time points. These FXI-related proteins were enriched in immune pathways related to causes of thrombo-inflammation, extracellular matrix interaction, lipid metabolism, and apoptosis. The results of this study offer important new avenues for future research into the multiple properties of FXI, which are of high clinical interest given the current development of FXI inhibitors.
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