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1. Cross-ancestry investigation of venousc genomic predictors

Author

Thibord, F., Klarin, D., Brody, J.A., Chen, M.H., Levin, M.G., Chasman, D.I., Goode, E.L., Hveem, K., Teder-Laving, M., Martinez-Perez, A., Aissi, D., Daian-Bacq, D., Ito, K., Natarajan, P., Lutsey, P.L., Nadkarni, G.N., Vries, P.S. de, Cuellar-Partida, G., Wolford, B.N., Pattee, J.W., Kooperberg, C., Braekkan, S.K., Li-Gao, R.F., Saut, N., Sept, C., Germain, M., Judy, R.L., Wiggins, K.L., Ko, D., O'Donnell, C.J., Taylor, K.D., Giulianini, F., Andrade, M. de, Nost, T.H., Boland, A., Empana, J.P., Koyama, S., Gilliland, T., R. do, Huffman, J.E., Wang, X., Zhou, W., Soria, J.M., Souto, J.C., Pankratz, N., Haessler, J., Hindberg, K., Rosendaal, F.R., Turman, C., Olaso, R., Kember, R.L., Bartz, T.M., Lynch, J.A., Heckbert, S.R., Armasu, S.M., Brumpton, B., Smadja, D.M., Jouven, X., Komuro, I., Clapham, K.R., Loos, R.J.F., Willer, C.J., Sabater-Lleal, M., Pankow, J.S., Reiner, A.P., Morelli, V.M., Ridker, P.M., Vlieg, A.V., Deleuze, J.F., Kraft, P., Rader, D.J., Lee, K.M., Psaty, B.M., Skogholt, A.H., Emmerich, J., Suchon, P., Rich, S.S., Vy, H.T., Tang, W.H., Jackson, R.D., Hansen, J.B., Morange, P.E., Kabrhel, C., Tregouet, D.A., Damrauer, S.M., Johnson, A.D., and Smith, N.L.

Subjects
meta-analysis, genome-wide association study, venous thromboembolism, genetics, venous thrombosis
Abstract

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Published
2022

2. Liver status and outcomes in patients without previous known liver disease receiving anticoagulant therapy for venous thromboembolism

Author

Martinez-Urbistondo D., de la Garza R. G., Villares-Fernandez P., Font C., Schellong S., Lopez-Nunez J. J., Gil-Diaz A., del Carmen Diaz-Pedroche M., Hirmerova J., Monreal M., Adarraga M., Aibar J., Alonso J., Amado C., Arcelus J., Asuero A., Ballaz A., Barba R., Barbagelata C., Barron M., Barron-Andres B., Blanco-Molina A., Beddar Chaib F., Botella E., Castro J., Chasco L., Criado J., de Ancos C., del Toro J., Demelo-Rodriguez P., Diaz-Brasero A., Diaz-Pedroche M., Diaz-Peromingo J., Di Campli M., Dubois-Silva A., Escribano J., Esposito F., Farfan-Sedano A., Fernandez-Capitan C., Fernandez-Reyes J., Fidalgo M., Flores K., Font L., Francisco I., Gabara C., Galeano-Valle F., Garcia M., Garcia-Bragado F., Garcia de Herreros M., de la Garza R., Garcia-Diaz C., Gomez-Cuervo C., Grau E., Guirado L., Gutierrez J., Hernandez-Blasco L., Jara-Palomares L., Jaras M., Jimenez D., Jimenez R., Jimenez-Alfaro C., Joya M., Lainez-Justo S., Lalueza A., Latorre A., Lima J., Lobo J., Lopez-Jimenez L., Lopez-Miguel P., Lopez-Nunez J., Lopez-Reyes R., Lopez-Saez J., Lorenzo A., Madridano O., Maestre A., Marchena P., Martin del Pozo M., Martin-Martos F., Mella C., Mercado M., Moises J., Munoz-Blanco A., Nieto J., Nofuentes-Perez E., Nunez-Fernandez M., Olid-Velilla M., Olivares M., Osorio J., Otalora S., Otero R., Paredes D., Pedrajas J., Porras J., Portillo J., Redondo I., Rodriguez-Matute C., Rosa V., Ruiz-Artacho P., Ruiz-Ruiz J., Salgueiro G., Sanchez-Martinez R., Sanchez-Munoz-Torrero J., Sancho T., Soler S., Suarez-Rodriguez B., Surinach J., Torres M., Torres-Sanchez A., Tolosa C., Trujillo-Santos J., Uresandi F., Valero B., Valle R., Varona J., Vela L., Vela J., Vidal G., Villalobos A., Villares P., Zamora C., Ay C., Nopp S., Pabinger I., Engelen M., Vanassche T., Verhamme P., Maly R., Accassat S., Ait Abdallah N., Bertoletti L., Bura-Riviere A., Catella J., Couturaud F., Crichi B., Debourdeau P., Espitia O., Farge-Bancel D., Grange C., Helfer H., Lacut K., Le Mao R., Mahe I., Morange P., Moustafa F., Poenou G., Sarlon-Bartoli G., Suchon P., Quere I., Braester A., Brenner B., Kenet G., Tzoran I., Basaglia M., Bilora F., Bortoluzzi C., Brandolin B., Ciammaichella M., De Angelis A., Di Micco P., Imbalzano E., Merla S., Pesavento R., Prandoni P., Siniscalchi C., Tufano A., Visona A., Vo Hong N., Zalunardo B., Nishimoto Y., Sato Y., Make K., Skride A., Strautmane S., Fonseca S., Martins F., Meireles J., Bosevski M., Bounameaux H., Mazzolai L., Caprini J., Bui H., Martinez-Urbistondo, D., de la Garza, R. G., Villares-Fernandez, P., Font, C., Schellong, S., Lopez-Nunez, J. J., Gil-Diaz, A., del Carmen Diaz-Pedroche, M., Hirmerova, J., Monreal, M., Adarraga, M., Aibar, J., Alonso, J., Amado, C., Arcelus, J., Asuero, A., Ballaz, A., Barba, R., Barbagelata, C., Barron, M., Barron-Andres, B., Blanco-Molina, A., Beddar Chaib, F., Botella, E., Castro, J., Chasco, L., Criado, J., de Ancos, C., del Toro, J., Demelo-Rodriguez, P., Diaz-Brasero, A., Diaz-Pedroche, M., Diaz-Peromingo, J., Di Campli, M., Dubois-Silva, A., Escribano, J., Esposito, F., Farfan-Sedano, A., Fernandez-Capitan, C., Fernandez-Reyes, J., Fidalgo, M., Flores, K., Font, L., Francisco, I., Gabara, C., Galeano-Valle, F., Garcia, M., Garcia-Bragado, F., Garcia de Herreros, M., de la Garza, R., Garcia-Diaz, C., Gomez-Cuervo, C., Grau, E., Guirado, L., Gutierrez, J., Hernandez-Blasco, L., Jara-Palomares, L., Jaras, M., Jimenez, D., Jimenez, R., Jimenez-Alfaro, C., Joya, M., Lainez-Justo, S., Lalueza, A., Latorre, A., Lima, J., Lobo, J., Lopez-Jimenez, L., Lopez-Miguel, P., Lopez-Nunez, J., Lopez-Reyes, R., Lopez-Saez, J., Lorenzo, A., Madridano, O., Maestre, A., Marchena, P., Martin del Pozo, M., Martin-Martos, F., Mella, C., Mercado, M., Moises, J., Munoz-Blanco, A., Nieto, J., Nofuentes-Perez, E., Nunez-Fernandez, M., Olid-Velilla, M., Olivares, M., Osorio, J., Otalora, S., Otero, R., Paredes, D., Pedrajas, J., Porras, J., Portillo, J., Redondo, I., Rodriguez-Matute, C., Rosa, V., Ruiz-Artacho, P., Ruiz-Ruiz, J., Salgueiro, G., Sanchez-Martinez, R., Sanchez-Munoz-Torrero, J., Sancho, T., Soler, S., Suarez-Rodriguez, B., Surinach, J., Torres, M., Torres-Sanchez, A., Tolosa, C., Trujillo-Santos, J., Uresandi, F., Valero, B., Valle, R., Varona, J., Vela, L., Vela, J., Vidal, G., Villalobos, A., Villares, P., Zamora, C., Ay, C., Nopp, S., Pabinger, I., Engelen, M., Vanassche, T., Verhamme, P., Maly, R., Accassat, S., Ait Abdallah, N., Bertoletti, L., Bura-Riviere, A., Catella, J., Couturaud, F., Crichi, B., Debourdeau, P., Espitia, O., Farge-Bancel, D., Grange, C., Helfer, H., Lacut, K., Le Mao, R., Mahe, I., Morange, P., Moustafa, F., Poenou, G., Sarlon-Bartoli, G., Suchon, P., Quere, I., Braester, A., Brenner, B., Kenet, G., Tzoran, I., Basaglia, M., Bilora, F., Bortoluzzi, C., Brandolin, B., Ciammaichella, M., De Angelis, A., Di Micco, P., Imbalzano, E., Merla, S., Pesavento, R., Prandoni, P., Siniscalchi, C., Tufano, A., Visona, A., Vo Hong, N., Zalunardo, B., Nishimoto, Y., Sato, Y., Make, K., Skride, A., Strautmane, S., Fonseca, S., Martins, F., Meireles, J., Bosevski, M., Bounameaux, H., Mazzolai, L., Caprini, J., and Bui, H.

Subjects
medicine.medical_specialty, VTE risk assessment, Healthy individual, Elevated liver enzymes, Hemorrhage, Gastroenterology, Liver disease, Recurrence, Fibrosis, Internal medicine, Internal Medicine, medicine, Anticoagulation adverse event, Humans, In patient, Registries, Clinical VTE, business.industry, Liver Diseases, Anticoagulants, Venous Thromboembolism, medicine.disease, Im - Original, Non-invasive liver assessment, Healthy individuals, Increased risk, Anticoagulant therapy, Emergency Medicine, Anticoagulation adverse events, business, Venous thromboembolism, Major bleeding
Abstract

The association between elevated liver enzymes or FIB-4 (fibrosis index 4) and outcome in patients with venous thromboembolism (VTE) has not been evaluated. Data from patients in RIETE (Registro Informatizado Enfermedad TromboEmbólica) were used to assess the association between elevated liver enzymes or FIB-4 levels and the rates of major bleeding or death in apparent liver disease-free patients with acute VTE under anticoagulation therapy. A total of 6206 patients with acute VTE and without liver disease were included. Of them, 92 patients had major bleeding and 168 died under anticoagulation therapy. On multivariable analysis, patients with elevated liver enzymes were at increased mortality risk (HR: 1.58; 95% CI: 1.10–2.28), while those with FIB-4 levels > 2.67 points were at increased risk for major bleeding (HR: 1.69; 95% CI: 1.04–2.74). Evaluation of liver enzymes and FIB-4 index at baseline in liver disease-free patients with VTE may provide additional information on the risk for major bleeding or death during anticoagulation. Supplementary Information The online version contains supplementary material available at 10.1007/s11739-021-02858-x.

Published
2021

3. Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism

Author

Lindstrom, S., Wang, L., Smith, E.N., Gordon, W., Vlieg, A.V., Andrade, M. de, Brody, J.A., Pattee, J.W., Haessler, J., Brumpton, B., Chasman, D.I., Suchon, P., Chen, M.H., Turman, C., Germain, M., Wiggins, K.L., MacDonald, J., Braekkan, S.K., Armasu, S.M., Pankratz, N., Jackson, R.D., Nielsen, J.B., Giulianini, F., Puurunen, M.K., Ibrahim, M., Heckbert, S.R., Damrauer, S.M., Natarajan, P., Klarin, D., Vries, P.S. de, Sabater-Lleal, M., Huffman, J.E., Bammler, T.K., Frazer, K.A., McCauley, B.M., Taylor, K., Pankow, J.S., Reiner, A.P., Gabrielsen, M.E., Deleuze, J.F., O'Donnell, C.J., Kim, J., McKnight, B., Kraft, P., Hansen, J.B., Rosendaal, F.R., Heit, J.A., Psaty, B.M., Tang, W.H., Kooperberg, C., Hveem, K., Ridker, P.M., Morange, P.E., Johnson, A.D., Kabrhel, C., Tregouet, D.A., Smith, N.L., Busenkell, E., Judy, R., Lynch, J., Levin, M., Aragam, J.H.K., Chaffin, M., Haas, M., Assimes, T.L., Huang, J., Lee, K.M., Shao, Q., Huang, Y.F., Sun, Y.V., Vujkovic, M., Saleheen, D., Miller, D.R., Reaven, P., DuVall, S., Boden, W., Pyarajan, S., Henke, P., Gaziano, J.M., Concato, J., Rader, D.J., Cho, K., Chang, K.M., Wilson, P.W.F., Tsao, P.S., Kathiresan, S., Obi, A., Million Veteran Program, CHARGE Hemostasis Working Grp, INVENT Consortium, Program in Genetic Epidemiology and Statistical Genetics (PGESG - BOSTON), Harvard School of Public Health, University of Washington [Seattle], The Scripps Translational Science Institute and Scripps Health, Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, University of Minnesota System, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Brigham and Women's Hospital [Boston], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), National Institutes of Health [Bethesda] (NIH), Harvard T.H. Chan School of Public Health, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biorobotics Lab (University of Washington), University of South-Eastern Norway (USN), Department of Health Sciences Research, Ohio State University [Columbus] (OSU), Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Los Angeles Biomedical Research Institute (LA BioMed), University of Augsburg [Augsburg], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Epidemiology, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, University of Minnesota [Twin Cities] (UMN), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), Department of Emergency Medicine, Massachusetts General Hospital [Boston], Universiteit Leiden-Universiteit Leiden, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Augsburg (UNIA), and Universiteit Leiden

Subjects
0301 basic medicine, Genetics, [SDV]Life Sciences [q-bio], Immunology, Genome-wide association study, Cell Biology, Hematology, 030204 cardiovascular system & hematology, Biology, equipment and supplies, Biochemistry, 3. Good health, Transcriptome, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Mendelian randomization, Expression quantitative trait loci, Gene expression, cardiovascular diseases, Gene, Genetic association, Whole blood
Abstract

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

Published
2019
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4. Image fusion-guided portal vein puncture during transjugular intrahepatic portosystemic shunt placement

Author

Montoya, J, Matta, N, Suchon, P, Guzian, M, Lambert, N, Mattei, J, Guis, S, Breban, M, Roudier, J, Balandraud, N, Rouabah, K., Varoquaux, A., Caporossi, J.M., Louis, G., Jacquier, A., Bartoli, J.M., Moulin, G., Vidal, V., Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Département de Radiologie [Hôpital de la Timone - APHM], and Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
Liver Cirrhosis, Male, medicine.medical_specialty, Computed Tomography Angiography, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Portal vein, Punctures, Esophageal and Gastric Varices, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Imaging, Three-Dimensional, 0302 clinical medicine, Image Processing, Computer-Assisted, medicine, Humans, Fluoroscopy, Radiology, Nuclear Medicine and imaging, Portography, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, Image fusion, Radiological and Ultrasound Technology, medicine.diagnostic_test, Portal Vein, business.industry, Radiation dose, Mean age, General Medicine, Middle Aged, Surgery, Computer-Assisted, 030220 oncology & carcinogenesis, Angiography, Feasibility Studies, Female, Radiology, Portasystemic Shunt, Transjugular Intrahepatic, business, Transjugular intrahepatic portosystemic shunt, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

The purpose of this study was to assess the feasibility and utility of image fusion (Easy-TIPS) obtained from pre-procedure CT angiography and per-procedure real-time fluoroscopy for portal vein puncture during transjugular intrahepatic portosystemic shunt (TIPS) placement.Eighteen patients (15 men, 3 women) with a mean age of 63 years (range: 48-81 years; median age, 65 years) were included in the study. All patients underwent TIPS placement by two groups of radiologists (one group with radiologists of an experience3 years and one with an experience≥3 years) using fusion imaging obtained from three-dimensional computed tomography angiography of the portal vein and real-time fluoroscopic images of the portal vein. Image fusion was used to guide the portal vein puncture during TIPS placement. At the end of the procedure, the interventional radiologists evaluated the utility of fusion imaging for portal vein puncture during TIPS placement. Mismatch between three-dimensional computed tomography angiography and real-time fluoroscopic images of the portal vein on image fusion was quantitatively analyzed. Posttreatment CT time, number of the puncture attempts, total radiation exposure and radiation from the retrograde portography were also recorded.Image fusion was considered useful for portal vein puncture in 13/18 TIPS procedures (72%). The mean posttreatment time to obtain fusion images was 16.4minutes. 3D volume rendered CT angiography images was strictly superimposed on direct portography in 10/18 procedures (56%). The mismatch mean value was 0.69cm in height and 0.28cm laterally. A mean number of 4.6 portal vein puncture attempts was made. Eight patients required less than three attempts. The mean radiation dose from retrograde portography was 421.2dGy.cmFusion imaging resulting from image fusion from pre-procedural CT angiography is feasible, safe and makes portal puncture easier during TIPS placement.

Published
2016
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5. Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism

Author

Lindstrom, S, Wang, L, Smith, EN, Gordon, W, Vlieg, AV, de Andrade, M, Brody, JA, Pattee, JW, Haessler, J, Brumpton, B, Chasman, DI, Suchon, P, Chen, MH, Turman, C, Germain, M, Wiggins, KL, MacDonald, J, Braekkan, SK, Armasu, SM, Pankratz, N, Jackson, RD, Nielsen, JB, Giulianini, F, Puurunen, MK, Ibrahim, M, Heckbert, SR, Damrauer, SM, Natarajan, P, Klarin, D, de Vries, PS, Sabater-Lleal, M, Huffman, JE, Bammler, TK, Frazer, KA, McCauley, BM, Taylor, K, Pankow, JS, Reiner, AP, Gabrielsen, ME, Deleuze, JF, O'Donnell, CJ, Kim, J, McKnight, B, Kraft, P, Hansen, JB, Rosendaal, FR, Heit, JA, Psaty, BM, Tang, WH, Kooperberg, C, Hveem, K, Ridker, PM, Morange, PE, Johnson, AD, Kabrhel, C, Tregouet, DA, Smith, NL, Busenkell, E, Judy, R, Lynch, J, Levin, M, Aragam, JHK, Chaffin, M, Haas, M, Assimes, TL, Huang, J, Lee, KM, Shao, Q, Huang, YF, Sun, YV, Vujkovic, M, Saleheen, D, Miller, DR, Reaven, P, DuVall, S, Boden, W, Pyarajan, S, Henke, P, Gaziano, JM, Concato, J, Rader, DJ, Cho, K, Chang, KM, Wilson, PWF, Tsao, PS, Kathiresan, S, Obi, A, Million Veteran Program, CHARGE Hemostasis Working Grp, and INVENT Consortium

Subjects
cardiovascular diseases, equipment and supplies
Abstract

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. Wemeta-analyzedGWAS data from18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

Published
2019

6. Genetic risk factors for venous thrombosis in women using combined oral contraceptives: update of the PILGRIM study

Author

Suchon, P., Al Frouh, F., Ibrahim, Marwa, Sarlon, G, Venton, G, Alessi, Marie-Christine, Trégouët, D-A, Morange, Pierre-Emmanuel, Goletto, Marie-Hélène, Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Aix-Marseille Université - Faculté de médecine (AMU MED), Aix Marseille Université (AMU), Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]

Subjects
Adult, Genotype, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Polymorphism, Single Nucleotide, Young Adult, Gene Frequency, genetic polymorphisms, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Risk Factors, Odds Ratio, Humans, Genetic Predisposition to Disease, Alleles, Factor XI, oral contraceptives, risk assessment, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Contraceptives, Oral, Combined, case control studies, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, venous thrombosis, Drug Monitoring
Abstract

International audience; Identifying women at risk of venous thrombosis (VT) under combined oral contraceptives (COC) is a major public health issue. The aim of this study was to investigate in COC users the impact on disease of genetic polymorphisms recently identified to associate with VT risk in the general population. Nine polymorphisms located on KNG1, F11, F5, F2, PROCR, FGG, TSPAN and SLC44A2 genes were genotyped in a sample of 766 patients and 464 controls as part of the PILGRIM (PILl Genetic Risk Monitoring) study. Cases were women who experienced an episode of documented VT during COC use, while controls were women with no history of VT using COC at the time of inclusion. Among the studied polymorphisms, only F11 rs2289252 was significantly associated with VT. The F11 rs2289252‐A allele was associated with a 1.6‐fold increased risk of VT (p < 0.0001). Besides, the combination of the rs2289252‐A allele with non‐O blood group, present in 52% of the cohort, was associated with an odds ratio of 4.00 (2.49–6.47; p < 10 −4). The consideration of this genetic risk factor could help to better assess the risk of VT in COC users. In women, the overall incidence of venous thrombosis (VT) is about 1.2 per 1000 person‐ years 1; this incidence being lower in women of reproductive age, with an estimate ranging between 0.4 and 0.6 per 1000 person‐years 1. The use of combined oral contraceptive (COC) is a major established risk factor for VT in women of reproductive age. The relative risk for COC use is about 3–6. It is well known that this risk depends on two major factors: the progestogen and the ethinyl estradiol dosage 2. It is estimated that more than 100 million women worldwide are using COC, making the impact of COC use on VT risk and public health of major importance 3. In France, 20 young women die annually of pulmonary embolism (PE) as a consequence of COC use 4. Furthermore, young and middle‐aged women with a personal history of VT have a 2.3‐fold increased risk of mortality 5. Besides, among survivors, 25–50% will have lasting debilitating health problems such as post‐thrombotic syndrome, severely hampering mobility and quality of life 6. Chronic thromboembolic pulmonary hypertension occurs in about 3% PE patients 7. Oral contraceptives and inherited thrombophilic defects (i.e. factor V Leiden and prothrombin mutations, deficiencies of protein C, protein S or antithrombin) are known to interact synergistically to increase the risk of VT 8. Very recently, we have found that the ABO blood group, an increasingly recognized risk factor for VT in the general population, was also associated with the risk of VT in COC users. In the PILGRIM (Pill Genetic Risk Monitoring) study, we observed that, under COC use, women of non‐O blood group displayed a 1.85‐fold increased risk of VT compared with O blood group carriers 9. Last year, the International VENous Thrombosis (INVENT) consortium presented the results of the first international meta‐analysis of genome‐wide association studies for VT in the general population 10. This project led to the identification of two unsuspected susceptibility

Published
2017
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8. Novel mechanisms regulating Factor XI plasma levels

Author

Sennblad, B., Basu, S., Mazur, J., Suchon, P., Martinez-Perez, A., Vlieg, Hylckama A., Truong, V., Li, Y., Gadin, J. R., Tang, W., Grossman, V., Handin, N., Franco-Cereceda, A., Pierre Morange, Maegdefessel, L., Gagnon, F., Soria, J. M., Eriksson, P., Hamsten, A., Rosendaal, F. R., Wild, P., Tregouet, D., Folsom, A., and Sabater-Lleal, M.

10. Heart Rate and Mortality in Patients With Acute Symptomatic Pulmonary Embolism

Author

G. Pellejero, Jose Gutierrez, R. Malý, M. Basaglia, L. Chasco, P. Suchon, R. Le Mao, Laurent Bertoletti, F. Martins, J. Caprini, A. Braester, F. Galeano-Valle, Hanh My Bui, J. Alonso, Y. Sato, G. Vidal, Y. Nishimoto, C. Tolosa, E. Nofuentes-Pérez, A.M. Díaz-Brasero, N. Ait Abdallah, M.D. Adarraga, R. Sánchez-Martínez, L. Font, Raquel López-Reyes, Inna Tzoran, Karine Lacut, J. del Toro, Andris Skride, Ana Jaureguizar, Joseph A. Caprini, C. Amado, R. García de la Garza, A.M. Camon, S. Merla, Luciano López-Jiménez, G. Salgueiro, Sebastian Schellong, Alfonso Muriel, F. Bilora, S. Lainez-Justo, B. Suárez-Rodríguez, Carme Font, F. Beddar Chaib, I. Francisco, C. Jiménez-Alfaro, P. Azcarate-Agüero, Maurizio Ciammaichella, J.A. Porras, N. Vo Hong, F. Martín-Martos, Dominique Farge-Bancel, D. Farge-Bancel, José Luis Lobo, M. Giménez-Suau, E. Grau, F. García-Bragado, Ángeles Blanco-Molina, Carmen Fernández-Capitán, María del Carmen Díaz-Pedroche, C. Grange, Adriana Visonà, L. Guirado, P. Villares, P. López-Miguel, José María Pedrajas, S. Accassat, Beatriz Valero, B. Crichi, Juan J. López-Núñez, Luis Jara-Palomares, G. Sarlon-Bartoli, J. Lima, C. Bortoluzzi, Alicia Lorenzo, C. de Ancos, M.A. Fidalgo, Philippe Debourdeau, Pablo Javier Marchena, C. Rodríguez-Matute, A.I. Farfán-Sedano, José Luis Fernández-Reyes, J.C. Escribano, Juan I. Arcelus, M. Barrón, I. Quere, Remedios Otero, A. De Angelis, P. Morange, Peter Verhamme, G. Kenet, P. Prandoni, Pedro Ruiz-Artacho, C. Siniscalchi, A. Zaicenko, M. Olid-Velilla, C. García-Díaz, B. Barrón-Andrés, T. Sancho, Fernando Uresandi, Javier Trujillo-Santos, A. Muñoz-Blanco, A. Villalobos, A. Dubois-Silva, J. Moisés, J. Osorio, M.I. Mercado, J.M. Suriñach, M.A. Aibar, M.D. Joya, Cihan Ay, J.A. Díaz-Peromingo, H. Bounameaux, Diego Martínez-Urbistondo, Thomas Vanassche, L. Bertoletti, Marijan Bosevski, Farès Moustafa, M. Martín del Pozo, J.F. Sánchez-Muñoz-Torrero, H.M. Bui, Ingrid Pabinger, M.C. Olivares, M. García de Herreros, M.J. Núñez-Fernández, B. Zalunardo, J.F. Varona, Stephan Nopp, Behnood Bikdeli, B. Brandolin, B. Bikdeli, Olga Madridano, Manuel Monreal, M.J. Jaras, Alessandra Bura-Rivière, Abílio Reis, J. Portillo, O. Espitia, J. Catella, Aitor Ballaz, F. Esposito, R. Barba, R. Valle, H. Helfer, I. Tzoran, J.B. López-Sáez, P. Ruiz-Artacho, M.A. García, J. Aibar, C. Gómez-Cuervo, C. Gabara, A. Latorre, J. Ruiz-Ruiz, Benjamin Brenner, S. Fonseca, S. Schellong, Raffaele Pesavento, Barry M. Brenner, Silvia Soler, Paolo Prandoni, Victor F. Tapson, Ana Maestre, Pierpaolo Di Micco, M. Muñoz, J. Criado, D. Jiménez, Antonella Tufano, G. Krstevski, B. Valero, Henri Bounameaux, M.I. Torres, G. Poenou, Isabelle Mahé, Aída Gil-Díaz, A. Asuero, S. Otalora, V. Rosa, L. Vela, E. Imbalzano, C. Vandenbriele, C. Barbagelata, Jana Hirmerova, J. Meireles, David Jiménez, Lucia Mazzolai, L. Hernández-Blasco, M. Bosevski, Gili Kenet, C. Mella, M. Monreal, J.R. Vela, P. Di Micco, Carlos Zamora, K. Flores, P. Demelo-Rodríguez, Radovan Malý, J. Birzulis, J.A. Nieto, J. Castro, M.V. Di Campli, Francis Couturaud, Raquel Barba, Jaureguizar, A., Jimenez, D., Bikdeli, B., Ruiz-Artacho, P., Muriel, A., Tapson, V., Lopez-Reyes, R., Valero, B., Kenet, G., Monreal, M., Prandoni, P., Brenner, B., Farge-Bancel, D., Barba, R., Di Micco, P., Bertoletti, L., Schellong, S., Tzoran, I., Reis, A., Bosevski, M., Bounameaux, H., Maly, R., Verhamme, P., Caprini, J. A., Bui, H. M., Adarraga, M. D., Aibar, J., Aibar, M. A., Alonso, J., Amado, C., Arcelus, J. I., Asuero, A., Azcarate-Aguero, P., Ballaz, A., Barbagelata, C., Barron, M., Barron-Andres, B., Blanco-Molina, A., Beddar Chaib, F., Camon, A. M., Castro, J., Chasco, L., Criado, J., de Ancos, C., del Toro, J., Demelo-Rodriguez, P., Diaz-Brasero, A. M., Diaz-Pedroche, M. C., Diaz-Peromingo, J. A., Di Campli, M. V., Dubois-Silva, A., Escribano, J. C., Esposito, F., Farfan-Sedano, A. I., Fernandez-Capitan, C., Fernandez-Reyes, J. L., Fidalgo, M. A., Flores, K., Font, C., Font, L., Francisco, I., Gabara, C., Galeano-Valle, F., Garcia, M. A., Garcia-Bragado, F., Garcia de Herreros, M., Garcia de la Garza, R., Garcia-Diaz, C., Gil-Diaz, A., Gomez-Cuervo, C., Gimenez-Suau, M., Grau, E., Guirado, L., Gutierrez, J., Hernandez-Blasco, L., Jara-Palomares, L., Jaras, M. J., Jimenez-Alfaro, C., Joya, M. D., Lainez-Justo, S., Latorre, A., Lima, J., Lobo, J. L., Lopez-Jimenez, L., Lopez-Miguel, P., Lopez-Nunez, J. J., Lopez-Saez, J. B., Lorenzo, A., Madridano, O., Maestre, A., Marchena, P. J., Martin del Pozo, M., Martin-Martos, F., Martinez-Urbistondo, D., Mella, C., Mercado, M. I., Moises, J., Munoz, M., Munoz-Blanco, A., Nieto, J. A., Nofuentes-Perez, E., Nunez-Fernandez, M. J., Olid-Velilla, M., Olivares, M. C., Osorio, J., Otalora, S., Otero, R., Pedrajas, J. M., Pellejero, G., Porras, J. A., Portillo, J., Rodriguez-Matute, C., Rosa, V., Ruiz-Ruiz, J., Salgueiro, G., Sanchez-Martinez, R., Sanchez-Munoz-Torrero, J. F., Sancho, T., Soler, S., Suarez-Rodriguez, B., Surinach, J. M., Torres, M. I., Tolosa, C., Trujillo-Santos, J., Uresandi, F., Valle, R., Varona, J. F., Vela, L., Vela, J. R., Vidal, G., Villalobos, A., Villares, P., Zamora, C., Ay, C., Nopp, S., Pabinger, I., Vanassche, T., Vandenbriele, C., Hirmerova, J., Accassat, S., Ait Abdallah, N., Bura-Riviere, A., Catella, J., Couturaud, F., Crichi, B., Debourdeau, P., Espitia, O., Grange, C., Helfer, H., Lacut, K., Le Mao, R., Mahe, I., Morange, P., Moustafa, F., Poenou, G., Sarlon-Bartoli, G., Suchon, P., Quere, I., Braester, A., Basaglia, M., Bilora, F., Bortoluzzi, C., Brandolin, B., Ciammaichella, M., De Angelis, A., Imbalzano, E., Merla, S., Pesavento, R., Siniscalchi, C., Tufano, A., Visona, A., Vo Hong, N., Zalunardo, B., Nishimoto, Y., Sato, Y., Birzulis, J., Skride, A., Zaicenko, A., Fonseca, S., Martins, F., Meireles, J., Krstevski, G., and Mazzolai, L.

Subjects
Male, Registrie, Pulmonary and Respiratory Medicine, medicine.medical_specialty, pulmonary embolism, Critical Care and Intensive Care Medicine, Logistic regression, Heart Rate, Internal medicine, Heart rate, medicine, In patient, Aged, Aged, 80 and over, business.industry, medicine.disease, mortality, Pulmonary embolism, Prospective Studie, Increased risk, Spain, Cardiology, Positive relationship, Female, Cardiology and Cardiovascular Medicine, business, Human
Abstract

Background: The association between heart rate (HR) and pulmonary embolism (PE) outcomes has not been well studied. Furthermore, optimal cutoffs to identify low-risk and intermediate- to high-risk patients are not well known. Research Question: Does an association exist between baseline HR and PE outcome across the continuum of HR values? Study Design and Methods: The current study included 44,331 consecutive nonhypotensive patients with symptomatic PE from the Registro Informatizado de la Enfermedad TromboEmbólica registry between 2001 and 2021. Outcomes included 30-day all-cause and PE-specific mortality. We used hierarchical logistic regression to assess the association between admission HR and outcomes. Results: A positive relationship was found between admission HR and 30-day all-cause and PE-related mortality. Considering an HR of 80 to 99 beats/min as a reference, patients in the higher HR strata showed higher rates of all-cause death (adjusted OR, 1.5 for HR of 100-109 beats/min; adjusted OR, 1.7 for HR of 110-119 beats/min; adjusted OR, 1.9 for HR of 120-139 beats/min; and adjusted OR, 2.4 for HR of ≥ 140 beats/min). Patients in the lower strata of HR showed significantly lower rates of 30-day all-cause mortality compared with the same reference group (adjusted OR, 0.6 for HR of 60-79 beats/min; and adjusted OR, 0.5 for HR of < 60 beats/min). The findings for 30-day PE-related mortality were similar. For identification of low-risk patients, a cutoff value of 80 beats/min (vs 110 beats/min) increased the sensitivity of the simplified Pulmonary Embolism Severity Index (sPESI) from 93.4% to 98.8%. For identification of intermediate- to high-risk patients, a cutoff value of 140 beats/min (vs 110 beats/min) increased the specificity of the Bova score from 93.2% to 98.0%. Interpretation: In nonhypotensive patients with acute symptomatic PE, a high HR portends an increased risk of all-cause and PE-related mortality. Modifying the HR cutoff in the sPESI and the Bova score improves prognostication of patients with PE.

Published
2022
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11. Variability of cut‐off values for the detection of lupus anticoagulants: results of an international multicenter multiplatform study

Author

S. Subramanian, A. Siegemund, Pierre Suchon, Elaine Gray, Michela Cini, Veena Chantarangkul, Marta Martinuzzo, Sophie Testa, Cristina Legnani, Katrien Devreese, J. S Dlott, Paola Pradella, Roberta Giacomello, Armando Tripodi, Università degli Studi di Milano [Milano] (UNIMI), Università degli Studi di Udine - University of Udine [Italie], Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli studi di Milano [Milano], Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli Studi di Milano = University of Milan (UNIMI), Tripodi, A, Chantarangkul, V, Cini, M, Devreese, K, Dlott, J S, Giacomello, R, Gray, E, Legnani, C, Martinuzzo, M E, Pradella, P, Siegemund, A, Subramanian, S, Suchon, P, and Testa, S

Subjects
Adult, Male, medicine.medical_specialty, Dilute Russell's viper venom time, Adolescent, Normal Distribution, 030204 cardiovascular system & hematology, Plasma, Young Adult, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Reference Values, Antiphospholipid syndrome, activated partial thromboplastin time, Statistics, dilute Russell viper venom test, medicine, Humans, Activated partial thromboplastin time, Dilute Russell viper venom test, Screening, Standardization, Hematology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Aged, standardization, Lupus anticoagulant, Systemic lupus erythematosus, medicine.diagnostic_test, business.industry, screening, Healthy subjects, Reproducibility of Results, Middle Aged, medicine.disease, Healthy Volunteers, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Surgery, Russell viper venom, Lupus Coagulation Inhibitor, 030220 oncology & carcinogenesis, Prothrombin Time, Female, Partial Thromboplastin Time, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Blood Coagulation Tests, Cut-off, business, antiphospholipid syndrome, Partial thromboplastin time
Abstract

Essentials Between-lab variations of cut-off values in lupus anticoagulant detection are unknown. Cut-off values were calculated in 11 labs each testing plasma from 120 donors with 3 platforms. Major variation was observed even within the same platform. Cut-off values determined in different labs are not interchangeable. SummaryBackground Cut-off values for interpretation of lupus anticoagulant (LA) detection are poorly investigated. Aims (i) To assess whether results from healthy donors were normally distributed and (ii) the between-laboratories differences in cut-off values for screening, mixing and LA confirmation when calculated as 99th or 95th centiles, and (iii) to assess their impact on the detection rate for LA. Methods Each of 11 laboratories using one of the three widely used commercial platforms for LA detection was asked to collect plasmas from 120 healthy donors and to perform screening, mixing and LA confirmation with two methods (activated partial thromboplastin time [APTT] and dilute Russell viper venom [dRVV]). A common set of LA-positive or LA-negative freeze-dried plasmas was used to assess the LA detection rate. Results were centralized (Milano) for statistical analysis. Results and conclusions (i) Clotting times or ratios for healthy subjects were not normally distributed in the majority of cases. The take-home message is that cut-off values should be determined preferably by the non-parametric method based on centiles. (ii) There were relatively large inter-laboratory cut-off variations even within the same platform and the variability was marginally attenuated when results were expressed as ratios (test-to-normal pooled plasma). The take-home message is that cut-off values should be determined locally. (iii) There were differences between cut-off values calculated as 99th or 95th centiles that translate into a different LA detection rate (the lower the centile the greater the detection rate). The take-home message is that cut-off values determined as the 95th centile allow a better LA detection rate.

Published
2017
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