17 research outputs found
An interaction map of circulating metabolites, immune gene networks, and their genetic regulation
Background: Immunometabolism plays a central role in many cardiometabolic diseases. However, a robust map of immune-related gene networks in circulating human cells, their interactions with metabolites, and their genetic control is still lacking. Here, we integrate blood transcriptomic, metabolomic, and genomic profiles from two population-based cohorts (total N = 2168), including a subset of individuals with matched multi-omic data at 7-year follow-up. Results: We identify topologically replicable gene networks enriched for diverse immune functions including cytotoxicity, viral response, B cell, platelet, neutrophil, and mast cell/basophil activity. These immune gene modules show complex patterns of association with 158 circulating metabolites, including lipoprotein subclasses, lipids, fatty acids, amino acids, small molecules, and CRP. Genome-wide scans for module expression quantitative trait loci (mQTLs) reveal five modules with mQTLs that have both cis and trans effects. The strongest mQTL is in ARHGEF3 (rs1354034) and affects a module enriched for platelet function, independent of platelet counts. Modules of mast cell/basophil and neutrophil function show temporally stable metabolite associations over 7-year follow-up, providing evidence that these modules and their constituent gene products may play central roles in metabolic inflammation. Furthermore, the strongest mQTL in ARHGEF3 also displays clear temporal stability, supporting widespread trans effects at this locus. Conclusions: This study provides a detailed map of natural variation at the blood immunometabolic interface and its genetic basis, and may facilitate subsequent studies to explain inter-individual variation in cardiometabolic disease.Peer reviewe
Relationship between lipoproteins, thrombosis and atrial fibrillation.
The prothrombotic state in atrial fibrillation (AF) occurs as a result of multifaceted interactions, known as Virchow's triad of hypercoagulability, structural abnormalities and blood stasis. More recently, there is emerging evidence that lipoproteins are implicated in this process, beyond their traditional role in atherosclerosis. In this review, we provide an overview of the various lipoproteins and explore the association between lipoproteins and AF, the effects of lipoproteins on haemostasis, and the potential contribution of lipoproteins to thrombogenesis in AF. There are several types of lipoproteins based on size, lipid composition and apolipoprotein category, namely: chylomicrons, very low density lipoprotein, low density lipoprotein (LDL), intermediate density lipoprotein and high density lipoprotein. Each of these lipoproteins may contain numerous lipid species and proteins with a variety of different functions. Furthermore, the lipoprotein particles may be oxidised causing an alteration in their structure and content. Of note, there is a paradoxical inverse relationship between total cholesterol and LDL-C levels, and incident AF. The mechanism by which this occurs may be related to the stabilising effect of cholesterol on myocardial membranes, along with its role in inflammation. Overall, specific lipoproteins may interact with haemostatic pathways to promote excess platelet activation and thrombin generation, as well as inhibiting fibrinolysis. In this regard, LDL-C has been shown to be an independent risk factor for thromboembolic events in AF. The complex relationship between lipoproteins, thrombosis and AF warrants further research with an aim to improve our knowledge base and contribute to our overall understanding of lipoprotein-mediated thrombosis
Combined use of rotational and excimer lASER coronary atherectomy (RASER) during complex coronary angioplastyâAn analysis of cases (2006â2016) from the British Cardiovascular Intervention Society database
The Impact of Intracoronary Imaging on PCI Outcomes in Cases Utilising Rotational Atherectomy: An Analysis of 8,417 Rotational Atherectomy Cases from the British Cardiovascular Intervention Society Database
A novel thromboxane A2 receptor D304N variant which abrogates ligand binding in a patient with a bleeding diathesis
Excimer laser coronary atherectomy during complex PCI: An analysis of 1,471 laser cases from the British Cardiovascular Intervention Society database
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Phosphatidylthreonine is a procoagulant lipid detected in human blood and elevated in coronary artery disease
Data availability:
All data produced in the present study are available upon reasonable request to the authors (contact Ali A. Hajeyah, [email protected]).Supplemental Data are available online at: https://www.sciencedirect.com/science/article/pii/S0022227523001578?via%3Dihub#sec5 and https://www.sciencedirect.com/science/article/pii/S0022227523001578?via%3Dihub#appsec1 .Aminophospholipids (aPL) such as phosphatidylserine are essential for supporting the activity of coagulation factors, circulating platelets, and blood cells. Phosphatidylthreonine (PT) is an aminophospholipid previously reported in eukaryotic parasites and animal cell cultures, but not yet in human tissues. Here, we evaluated whether PT is present in blood cells and characterized its ability to support coagulation. Several PT molecular species were detected in human blood, washed platelets, extracellular vesicles, and isolated leukocytes from healthy volunteers using liquid chromatographyâtandem mass spectrometry. The ability of PT to support coagulation was demonstrated in vitro using biochemical and biophysical assays. In liposomes, PT supported prothrombinase activity in the presence and absence of phosphatidylserine. PT nanodiscs strongly bound FVa and lactadherin (nM affinity) but poorly bound prothrombin and FX, suggesting that PT supports prothrombinase through recruitment of FVa. PT liposomes bearing tissue factor poorly generated thrombin in platelet poor plasma, indicating that PT poorly supports extrinsic tenase activity. On platelet activation, PT is externalized and partially metabolized. Last, PT was significantly higher in platelets and extracellular vesicle from patients with coronary artery disease than in healthy controls. In summary, PT is present in human blood, binds FVa and lactadherin, supports coagulation in vitro through FVa binding, and is elevated in atherosclerotic vascular disease. Our studies reveal a new phospholipid subclass, that contributes to the procoagulant membrane, and may support thrombosis in patients at elevated risk.A. A. H. acknowledges funding from Kuwait University and support from Kuwait Cultural Office (KCO) in London. M. B. P. was funded by the Wellcome Trust (GW4-CAT fellowship 216278/Z/19/Z) and Academy of Medical Sciences Starter Grant (SGL026â1037). D. C., P. W. C., and V. B. O. D. acknowledge funding from British Heart Foundation (Programme Grant RG/F/20/110020). Funding from EU Marie Sklodowska-Curie ITN ArthritisHeal is acknowledged (V. B. O. D., D. C.). D. P. and J. H. M. acknowledge support from the NIH Common Fund (Grant R01 GM123455) and the National Heart, Lung, and Blood Institute of NIH (Grant R35 HL135823)