Whole-exome sequencing identifies rare variants in STAB2 associated with venous thromboembolic disease

Desch, Karl C.; Ozel, Ayse Bilge; Halvorsen, Matthew; Jacobi, Paula M.; Golden, Krista; Underwood, Mary; Germain, Marine; Trégouët, David‐Alexandre; Reitsma, Pieter H.; Kearon, Clive; Mokry, Lauren; Richards, J. Brent; Williams, Frances; Li, Jun Z.; Goldstein, David B.; Ginsburg, David

doi:10.1182/blood.2019004161

Cited by 44 publications

(57 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cai et al [ 123 ], Mo et al [ 124 ], Sun et al [ 125 ], Martinelli et al [ 126 ], Zhao et al [ 127 ], Assimes et al [ 128 ] and Piechota et al [ 129 ] showed that CCR7, FCN1, ESM1, F8 (coagulation factor VIII), C1QTNF1, ALOX5 and MSR1 were an important target gene for coronary artery disease. STAB2 have been suggested to be associated with venous thromboembolic disease [ 130 ]. Genes such as COMP (cartilage oligomeric matrix protein) [ 131 ], CHI3L1 [ 132 ], PLA2G2A [ 133 ], P2RY12 [ 134 ], CR1 [ 135 ], HPSE (heparanase) [ 136 ], PTX3 [ 137 ] and SERPINE1 [ 138 ] were related to atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Identification of candidate biomarkers and therapeutic agents for heart failure by bioinformatics analysis

Kolur¹,

Vastrad²,

Vastrad

et al. 2021

BMC Cardiovasc Disord

View full text Add to dashboard Cite

Introduction Heart failure (HF) is a heterogeneous clinical syndrome and affects millions of people all over the world. HF occurs when the cardiac overload and injury, which is a worldwide complaint. The aim of this study was to screen and verify hub genes involved in developmental HF as well as to explore active drug molecules. Methods The expression profiling by high throughput sequencing of GSE141910 dataset was downloaded from the Gene Expression Omnibus (GEO) database, which contained 366 samples, including 200 heart failure samples and 166 non heart failure samples. The raw data was integrated to find differentially expressed genes (DEGs) and were further analyzed with bioinformatics analysis. Gene ontology (GO) and REACTOME enrichment analyses were performed via ToppGene; protein–protein interaction (PPI) networks of the DEGs was constructed based on data from the HiPPIE interactome database; modules analysis was performed; target gene—miRNA regulatory network and target gene—TF regulatory network were constructed and analyzed; hub genes were validated; molecular docking studies was performed. Results A total of 881 DEGs, including 442 up regulated genes and 439 down regulated genes were observed. Most of the DEGs were significantly enriched in biological adhesion, extracellular matrix, signaling receptor binding, secretion, intrinsic component of plasma membrane, signaling receptor activity, extracellular matrix organization and neutrophil degranulation. The top hub genes ESR1, PYHIN1, PPP2R2B, LCK, TP63, PCLAF, CFTR, TK1, ECT2 and FKBP5 were identified from the PPI network. Module analysis revealed that HF was associated with adaptive immune system and neutrophil degranulation. The target genes, miRNAs and TFs were identified from the target gene—miRNA regulatory network and target gene—TF regulatory network. Furthermore, receiver operating characteristic (ROC) curve analysis and RT-PCR analysis revealed that ESR1, PYHIN1, PPP2R2B, LCK, TP63, PCLAF, CFTR, TK1, ECT2 and FKBP5 might serve as prognostic, diagnostic biomarkers and therapeutic target for HF. The predicted targets of these active molecules were then confirmed. Conclusion The current investigation identified a series of key genes and pathways that might be involved in the progression of HF, providing a new understanding of the underlying molecular mechanisms of HF.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of candidate biomarkers and therapeutic agents for heart failure by bioinformatics analysis

Kolur¹,

Vastrad²,

Vastrad

et al. 2021

BMC Cardiovasc Disord

View full text Add to dashboard Cite

show abstract

“…29 Importantly, and as highlighted in other parts of this review, interspecies conclusions should be made with caution, and despite the high level of homology between mouse and human VWFpp AA sequences (86%), plasma levels of VWFpp are not elevated in humans known to be heterozygous for loss-of-function stabilin-2 variants. 30 While we are only very recently learning about the details of how and where the VWFpp is cleared from the circulation, measurement of VWFpp levels in plasma has been used for several years as a biomarker of certain pathophysiologic states. Concomitant increases in VWFpp and mature VWF: Ag are found in situations of acute endothelial activation such as thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, sepsis, and severe malaria.…”

Section: Clearance Of the Vwf Propeptide And Its Role As Biomarkermentioning

confidence: 99%

Functional Roles of the von Willebrand Factor Propeptide

Rawley

Lillicrap

2021

Hamostaseologie

View full text Add to dashboard Cite

The primary polypeptide sequence of von Willebrand factor (VWF) includes an N-terminal 741-amino acid VWF propeptide (VWFpp). In cells expressing VWF, the VWFpp performs two critical functions. In the Golgi, VWFpp mediates the intermolecular disulfide linkages that generate high-molecular-weight VWF multimers. Subsequently, the VWFpp, which is proteolytically cleaved from mature VWF by furin, functions to generate the endothelial storage organelles (Weibel-Palade bodies) in which VWF and a distinct collection of proteins are stored, and from where they undergo regulated secretion from the endothelium. The VWFpp is secreted from endothelial cells as dimers and circulates in plasma with at least some of the dimers associating with a noncovalent manner with the D′D3 domain of mature VWF. The VWFpp has a half-life of 2 to 3 hours in plasma, but to date no extracellular function has been determined for the molecule. Nevertheless, its large size and several biologically interesting structural features (two sets of vicinal cysteines and an RGD sequence) suggest that there may be roles that the VWFpp plays in hemostasis or associated physiological processes such as angiogenesis or wound repair.

show abstract

“…As a strategy to identify candidate variants that could explain the VTE phenotype in individuals with discordant class prediction, we first prioritized variants that were likely functional (stop loss/stop gain, frameshift, non-synonymous and splicing variants), located in known VTE associated genes (ABO, ARID4A, C4BPB, EIF5A, F2, F3, F5, F8, F9, F13A1, FGG, GRK5, MPHOSPH9, MAST2, NUGCC, OSMR, PLAT, PLCG2, PLEK1, PROC, PROS1, SCARA5, SERPINC1, SLC44A2, STAB2, STX10, STXBP5, THBD, TSPAN15, VWF) [56][57][58], that have not been reported or at a low frequency (<1‰) in public genomic data repositories (dbSNP, GnomAD) and that was present in only one of the sequenced patients. If no candidate variants was identified in known VTE genes, we extended our search to whole coding genes and also took into account the predicted deleteriousness of selected candidates using in silico tools such as SIFT, PolyPhen and CADD-v1.2 [59]…”

Section: Nmentioning

confidence: 99%

An artificial neural network approach integrating plasma proteomics and genetic data identifies PLXNA4 as a new susceptibility locus for pulmonary embolism

Razzaq

Iglesias

Ibrahim‐Kosta

et al. 2020

Preprint

View full text Add to dashboard Cite

Venous thromboembolism is the third common cardiovascular disease and is composed of two entities, deep vein thrombosis (DVT) and its fatal form, pulmonary embolism (PE). While PE is observed in ~40% of patients with documented DVT, there is limited biomarkers that can help identifying patients at high PE risk. To fill this need, we implemented a two hidden-layers artificial neural networks (ANN) on 376 antibodies and 19 biological traits measured in the plasma of 1388 DVT patients, with or without PE, of the MARTHA study. We used the LIME algorithm to obtain a linear approximate of the resulting ANN prediction model. As MARTHA patients were typed for genotyping DNA arrays, a genome wide association study (GWAS) was conducted on the LIME estimate. Detected single nucleotide polymorphisms (SNPs) were tested for association with PE risk in MARTHA. Main findings were replicated in the EOVT study composed of 143 PE patients and 196 DVT only patients. The derived ANN model for PE achieved an accuracy of 0.89 and 0.79 in our training and testing sets, respectively. A GWAS on the LIME approximate identified a strong statistical association peak (p = 5.3x10-7) at the PLXNA4 locus, with lead SNP rs1424597 at which the minor A allele was further shown to associate with an increased risk of PE (OR = 1.49 [1.12 − 1.98], p = 6.1x10-3). Further association analysis in EOVT revealed that, in the combined MARTHA and EOVT samples, the rs1424597-A allele was associated with increased PE risk (OR = 1.74 [1.27 − 2.38, p = 5.42x10-4) in patients over 37 years of age but not in younger patients (OR = 0.96 [0.65 − 1.41], p = 0.848). Using an original integrated proteomics and genetics strategy, we identified PLXNA4 as a new susceptibility gene for PE whose exact role now needs to be further elucidated.

show abstract

Whole-exome sequencing identifies rare variants in STAB2 associated with venous thromboembolic disease

Cited by 44 publications

References 47 publications

Identification of candidate biomarkers and therapeutic agents for heart failure by bioinformatics analysis

Identification of candidate biomarkers and therapeutic agents for heart failure by bioinformatics analysis

Functional Roles of the von Willebrand Factor Propeptide

An artificial neural network approach integrating plasma proteomics and genetic data identifies PLXNA4 as a new susceptibility locus for pulmonary embolism

Contact Info

Product

Resources

About