Project description:Overview: Our overall long-term goal is to determine risk factors for the complex (multifactorial) disease, venous thromboembolism (VTE), that will allow physicians to stratify individual patient risk and target VTE prophylaxis to those who would benefit most. In this genome-wide association case-control study (1300 cases and 1300 controls) we hope to identify susceptibility variants for VTE. Mutations within genes encoding for important components of the anticoagulant, procoagulant, fibrinolytic, and innate immunity pathways are risk factors for VTE. We hypothesize that other genes within these four pathways or within other pathways also are VTE disease-susceptibility genes. Therefore, we performed a genome wide association (GWA) screen and analysis using the Illumina 660W platform to identify SNPs within 1,300 clinic-based, non-cancer VTE cases primarily from Minnesota and the upper Midwest USA, and 1300 clinic-based, unrelated controls frequency-matched on patient age, gender, myocardial infarction/stroke status and state of residence. This is a subset of a slightly larger candidate gene study using 1500 case-control pairs to identify haplotype-tagging SNPs (ht-SNPs) in a large set of candidate genes (n~750) within the anticoagulant, procoagulant, fibrinolytic, and innate immunity pathways. Study Populations. Cases. VTE cases were consecutive Mayo Clinic outpatients with objectively-diagnosed deep vein thrombosis (DVT) and/or pulmonary embolism (PE) residing in the upper Midwest and referred by Mayo Clinic physician to the Mayo Clinic Special Coagulation Laboratory for clinical diagnostic testing to evaluate for an acquired or inherited thrombophilia, or to the Mayo Clinic Thrombophilia Center. Any person contacted to be a control but discovered to have had a VTE was evaluated for inclusion as a case. Cases were primarily residents from Minnesota, Wisconsin, Iowa, Michigan, Illinois, North or South Dakota, Nebraska, Kansas, Missouri and Indiana. A DVT or PE was categorized as objectively diagnosed when (a) confirmed by venography or pulmonary angiography, or pathology examination of thrombus removed at surgery, or (b) if at least one non-invasive test (compression duplex ultrasonography, lung scan, computed tomography scan, magnetic resonance imaging) was positive. A VTE was defined as: <ol> <li>Proximal leg deep vein thrombosis (DVT), which includes the common iliac, internal iliac, external iliac, common femoral, superficial [now termed "femoral"] femoral, deep femoral [sometimes referred to as "profunda" femoral] and/or popliteal veins. (Note: greater and lesser saphenous veins, or other superficial or perforator veins, were not included as proximal or distal leg DVT).</li> <li>Distal leg DVT (or "isolated calf DVT"), which includes the anterior tibial, posterior tibial and/or peroneal veins. (Note: gastrocnemius, soleal and/or sural [e.g., "deep muscular veins" of the calf] vein thrombosis was not included as distal leg DVT).</li> <li>Arm DVT, which includes the axillary, subclavian and/or innominate (brachiocephalic) veins. (Note: jugular [internal or external], cephalic and brachial vein thrombosis was not included in "arm DVT").</li> <li>Hepatic, portal, splenic, superior or inferior mesenteric, and/or renal vein thrombosis. (Note: ovarian, testicular, peri-prostatic and/or pelvic vein thrombosis was not included).</li> <li>Cerebral vein thrombosis (includes cerebral or dural sinus or vein, saggital sinus or vein, and/or transverse sinus or vein thrombosis).</li> <li>Inferior vena cava (IVC) thrombosis</li> <li>Superior vena cava (SVC) thrombosis</li> <li>Pulmonary embolism</li> </ol> Patients with VTE related to active cancer, antiphospholipid syndrome, inflammatory bowel disease, vasculitis, a rheumatoid or other autoimmune disorder, a vascular anomaly (e.g., Klippel-Trénaunay syndrome, etc.), heparin-induced thrombocytopenia, or a mechanical cause for DVT (e.g., arm DVT or SVC thrombosis related to a central venous catheter or transvenous pacemaker, portal and/or splenic vein thrombosis related to liver cirrhosis, IVC thrombosis related to retroperitoneal fibrosis, etc.), with hemodialysis arteriovenous fistula thrombosis, or with prior liver or bone marrow transplantation were excluded. Controls. A Mayo Clinic outpatient control group was prospectively recruited for this study. Controls were frequency-matched on the age group (18-29, 30-39, 40-49, 50-59, 60-69, 70-79, and 80+ years), sex, myocardial infarction/stroke status, and state of residence distribution of the cases. We selected clinic-based controls using a controls' database of persons undergoing general medical examinations in the Mayo Clinic Departments of General Internal Medicine or Primary Care Internal Medicine. Additionally persons undergoing evaluation at the Mayo Clinic Sports Medicine Center, and the Department of Family Medicine were screened for inclusion as controls. This study is part of the Gene Environment Association Studies initiative (GENEVA, <a href="http://www.genevastudy.org" target="_blank">http://www.genevastudy.org</a>) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to venous thrombosis through large-scale genome-wide association studies of 1,300 clinic-based, VTE cases and 1300 clinic-based, unrelated controls. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

Project description:Antiphospholipid syndrome (APS) is associated with arterial and venous thrombosis. The unfavorable fibrin clot phenotype, including formation of dense and poorly lysable clots, has been reported both in thrombotic APS and venous thromboembolism (VTE). The presence and amount of different proteins within a plasma clot, not only associated with the coagulation system, may influence clot properties. To our knowledge, there is a lack of data on plasma fibrin-clot bound proteins in patients with thrombotic APS or VTE. The aim of our study was to perform a quantitative proteomic analysis of fibrin clots prepared from citrated plasma from subjects with thrombotic APS and prior VTE, along with fibrin clot permeability (Ks) and clot lysis time (CLT) assessed ex vivo. We investigated 23 consecutive patients with APS, 18 with a history of first-ever VTE, and 20 age and sex matched healthy subjects. A multiple enzyme digestion filter aided sample preparation and a multienzyme digestion (MED) FASP method combined with LC-MS/MS analysis performed on a Proxeon Easy-nLC System coupled to the Q Exactive HF mass spectrometer were used. The proteomic analysis revealed that clot composition regarding 117 proteins in APS patients and 48 proteins in VTE patients was changed as compared to healthy controls, while 72 clot-bounded proteins differed between APS and VTE subjects. In healthy controls, Ks was associated with fibrinogen alpha and gamma chains (r=0.46 and r=0.46, both p<0.05, respectively) or apolipoprotein B-100 (r=-0.53, p<0.05), while CLT correlated with annexin A2 (r=-0.58, p<0.05), apolipoportein(a) (r=0.47, p<0.05), or platelet glycoprotein 4 (r=0.59, p<0.05). In VTE patients correlations of Ks with complement C1q and histone H2B, as factors closely linked with thrombosis, were observed (r=-0.52 and r=-0.47, both p<0.05, respectively). In patients with thrombotic APS all above-mentioned associations were not found. This study is the first to show that different proteins are able to influence the clot formation, structure, and properties. Since, prothrombotic conditions abolished associations observed in healthy subjects fibrin clots, differences in protein clot components might explain the links between prothrombotic fibrin clot phenotype and thromboembolic events.

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GENEVA GWAS of Venous Thrombosis

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