Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease

Klarin, Derek; Busenkell, Emma; Judy, Renae; Lynch, Julie; Levin, Michael G.; Haessler, Jeffery; Aragam, Krishna; Chaffin, Mark; Haas, Mary E.; Lindström, Sara; Assimes, Themistocles L.; Huang, Jie; Lee, Kyung M.; Shao, Qing; Huffman, Jennifer E.; Kabrhel, Christopher; Huang, Yunfeng; Sun, Yan V.; Vujkovic, Marijana; Saleheen, Danish; Miller, Donald R.; Reaven, Peter D.; DuVall, Scott L.; Boden, William E.; Pyarajan, Saiju; Reiner, Alex P.; Trégouët, David‐Alexandre; Henke, Peter K.; Kooperberg, Charles; Gaziano, J. Michael; Concato, John; Rader, Daniel J.; Cho, Kelly; Chang, Kyong–Mi; Wilson, Peter W.F.; Smith, Nicholas L.; O’Donnell, Christopher J.; Tsao, Philip S.; Kathiresan, Sekar; Obi, Andrea; Damrauer, Scott M.; Natarajan, Pradeep

doi:10.1038/s41588-019-0519-3

Cited by 164 publications

(230 citation statements)

References 51 publications

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“…We first tested whether any of the cis-pQTLs or proxies in high LD (r²>0.8) have been reported in the GWAS catalogue and identified links between genetically verified drug targets and corresponding indications for lead cis-pQTLs at F2 (rs1799963 associated with venous thrombosis 28 ), IL6R (rs2228145 with rheumatoid arthritis 29 ), and PLG (rs4252185 associated with coronary artery disease 30 ).…”

Section: Linking Cis-pqtls To Clinical Outcomesmentioning

confidence: 99%

Genetic architecture of host proteins interacting with SARS-CoV-2

Pietzner

Wheeler

Carrasco-Zanini

et al. 2020

Preprint

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ABSTRACTStrategies to develop therapeutics for SARS-CoV-2 infection may be informed by experimental identification of viral-host protein interactions in cellular assays and measurement of host response proteins in COVID-19 patients. Identification of genetic variants that influence the level or activity of these proteins in the host could enable rapid ‘in silico’ assessment in human genetic studies of their causal relevance as molecular targets for new or repurposed drugs to treat COVID-19. We integrated large-scale genomic and aptamer-based plasma proteomic data from 10,708 individuals to characterize the genetic architecture of 179 host proteins reported to interact with SARS-CoV-2 proteins or to participate in the host response to COVID-19. We identified 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links, evidence that putative viral interaction partners such as MARK3 affect immune response, and establish the first link between a recently reported variant for respiratory failure of COVID-19 patients at the ABO locus and hypercoagulation, i.e. maladaptive host response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and dynamic and detailed interrogation of results is facilitated through an interactive webserver (https://omicscience.org/apps/covidpgwas/).

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Section: Linking Cis-pqtls To Clinical Outcomesmentioning

confidence: 99%

Genetic architecture of host proteins interacting with SARS-CoV-2

Pietzner

Wheeler

Carrasco-Zanini

et al. 2020

Preprint

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“…PAI-1 inhibits fibrinolysis by cleaving tPA and uPA via the serine protease mechanism [198]. This gene's expression is strongly linked to VTE within large Genome Wide Association Studies (GWAS) and mice overexpressing PAI-1 form 50% larger thrombus than mice with PAI-1 deficiency [199][200][201]. However, animal studies of PAI-1 inhibition have been mixed.…”

Section: Fibrinolysismentioning

confidence: 99%

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms

Nicklas

Gordon

Henke

2020

IJMS

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Venous thromboembolism (VTE) is a pathology encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE) associated with high morbidity and mortality. Because patients often present after a thrombus has already formed, the mechanisms that drive DVT resolution are being investigated in search of treatment. Herein, we review the current literature, including the molecular mechanisms of fibrinolysis and collagenolysis, as well as the critical cellular roles of macrophages, neutrophils, and endothelial cells. We propose two general models for the operation of the immune system in the context of venous thrombosis. In early thrombus resolution, neutrophil influx stabilizes the tissue through NETosis. Meanwhile, macrophages and intact neutrophils recognize the extracellular DNA by the TLR9 receptor and induce fibrosis, a complimentary stabilization method. At later stages of resolution, pro-inflammatory macrophages police the thrombus for pathogens, a role supported by both T-cells and mast cells. Once they verify sterility, these macrophages transform into their pro-resolving phenotype. Endothelial cells both coat the stabilized thrombus, a necessary early step, and can undergo an endothelial-mesenchymal transition, which impedes DVT resolution. Several of these interactions hold promise for future therapy. already progressed past the point of anticoagulant efficacy [12,13]. Thus, there is potential clinical utility in investigating and controlling the process by which DVTs resolve in order to provide better care to these later-stage patients, with less bleeding risk. Overview of Venous Thrombus Development in HumansThe time sequence of DVT development and resolution was correctly suggested as early as 1962, based on empirical stains that detected changes in the nanoscopic roughness of clotted material [14]. As Lendrum et. al. remarked, "we consider that the intracytoplasmic granules, which we think are engulfed fibrin, seen in pulmonary phagocytes and in the endothelium of arteries and veins containing thrombus, are better shown by this (methyl-scarlet-blue) method than by any of the others." In fresh clot (whether in deep veins or in diabetic kidneys), platelets and erythrocytes are initially linked in a fine mesh yielding a relatively smooth surface (stage 1). A mat of the medium-textured fibrin replaces the initial thrombus (stage 2), which is gradually replaced by much coarser collagen (stage 3). This staging of clot development quickly became the basis of a pathological guide to grade thrombi [15]. The current three-stage refinement of the DVT grading scheme indicates that the turnover of erythrocyte-rich to fibrin-rich clot in humans is complete approximately seven days after the initial thrombotic event [16], whereas fibrin deposition commences after one day [17]. Various leukocytes, initially neutrophils and later macrophages, are believed to control this progression of DVTs development from a mass of erythrocytes, to fibrin, and finally to collagen [18]. Infiltrating T-lymphocytes and macrophages conta...

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“…Interestingly, Klarin et al (2017 ) recently reported an association between the T allele of rs6993770 and decreased risk of venous thromboembolism (VTE). They postulated that the underlying mechanism is a ZFPM2 mediated decrease in the plasma concentration of the principal inhibitor of plasminogen activator PAI-1, which is encoded by SERPINE1 (Klarin et al 2019) . The notion that lower levels of plasma PAI-1 cause a reduced risk of VTE is biologically plausible.…”

Section: Evidence That Zfpm2 Is a Regulator Of Platelet α-Granularitymentioning

confidence: 99%

Genetic Analyses of Blood Cell Structure for Biological and Pharmacological Inference

Akbari

Vuckovic

Jiang

et al. 2020

Preprint

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Thousands of genetic associations with phenotypes of blood cells are known, but few are with phenotypes relevant to cell function. We performed GWAS of 63 flow-cytometry phenotypes, including measures of cell granularity, nucleic acid content, and reactivity, in 39,656 participants in the INTERVAL study, identifying 2,172 variant-trait associations. These include associations mediated by functional cellular structures such as secretory granules, implicated in vascular, thrombotic, inflammatory and neoplastic diseases. By integrating our results with epigenetic data and with signals from molecular abundance/disease GWAS, we infer the hematopoietic origins of population phenotypic variation and identify the transcription factor FOG2 as a regulator of platelet α-granularity. We show how flow cytometry genetics can suggest cell types mediating complex disease risk and suggest efficacious drug targets, presenting Daclizumab/Vedolizumab in autoimmune disease as positive controls. Finally, we add to existing evidence supporting IL7/IL7-R as drug targets for multiple sclerosis.

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Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease

Cited by 164 publications

References 51 publications

Genetic architecture of host proteins interacting with SARS-CoV-2

Genetic architecture of host proteins interacting with SARS-CoV-2

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms

Genetic Analyses of Blood Cell Structure for Biological and Pharmacological Inference

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