8 results on '"Ares Rocanin Arjo"'
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2. Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma
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Mary Tsikitis, Spyros Zakynthinos, Yu Amanda Guo, Vassili Soumelis, George Kollias, Georgios T. Stathopoulos, Ioannis Kalomenidis, Konstantinos Potaris, Giannoula Ntaliarda, Georgios Kazamias, Ares Rocanin Arjo, Maria Tsoumakidou, Ioanna Giopanou, Dimitra Kerdidani, and Panagiotis Chouvardas
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0301 basic medicine ,Chemokine ,Adoptive cell transfer ,T-Lymphocytes ,animal diseases ,General Physics and Astronomy ,02 engineering and technology ,Adaptive Immunity ,lcsh:Science ,Multidisciplinary ,biology ,021001 nanoscience & nanotechnology ,Acquired immune system ,Adoptive Transfer ,3. Good health ,Up-Regulation ,medicine.anatomical_structure ,embryonic structures ,RNA Interference ,Chemokines ,0210 nano-technology ,Signal Transduction ,animal structures ,T cell ,Science ,Adenocarcinoma of Lung ,chemical and pharmacologic phenomena ,Wnt1 Protein ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Paracrine signalling ,Cell Line, Tumor ,medicine ,Gene silencing ,Animals ,Humans ,Gene Silencing ,Cell Proliferation ,Immune Evasion ,Cell growth ,General Chemistry ,Dendritic Cells ,biochemical phenomena, metabolism, and nutrition ,Mice, Inbred C57BL ,030104 developmental biology ,Cancer cell ,biology.protein ,Cancer research ,bacteria ,lcsh:Q - Abstract
Lung adenocarcinoma (LUAD)-derived Wnts increase cancer cell proliferative/stemness potential, but whether they impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. In TCGA, Wnt1 correlates strongly with tolerogenic genes. In another LUAD cohort, Wnt1 inversely associates with T cell abundance. Altering Wnt1 expression profoundly affects growth of murine lung adenocarcinomas and this is dependent on conventional dendritic cells (cDCs) and T cells. Mechanistically, Wnt1 leads to transcriptional silencing of CC/CXC chemokines in cDCs, T cell exclusion and cross-tolerance. Wnt-target genes are up-regulated in human intratumoral cDCs and decrease upon silencing Wnt1, accompanied by enhanced T cell cytotoxicity. siWnt1-nanoparticles given as single therapy or part of combinatorial immunotherapies act at both arms of the cancer-immune ecosystem to halt tumor growth. Collectively, our studies show that Wnt1 induces immunologically cold tumors through cDCs and highlight its immunotherapeutic targeting., The Wnt pathway regulates anti-tumour immunity in melanoma. Here, the authors show that, in lung adenocarcinoma, secretion of the ligand Wnt1 induces immune resistance by impairing the ability of dendritic cells to cross-prime T cells, and that blocking Wnt signalling enhances rejection of tumours by acting both on the cancer and immune cells.
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- 2019
3. Genome-wide investigation of DNA methylation marks associated with FV Leiden mutation.
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Dylan Aïssi, Jessica Dennis, Martin Ladouceur, Vinh Truong, Nora Zwingerman, Ares Rocanin-Arjo, Marine Germain, Tara A Paton, Pierre-Emmanuel Morange, France Gagnon, and David-Alexandre Trégouët
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Medicine ,Science - Abstract
In order to investigate whether DNA methylation marks could contribute to the incomplete penetrance of the FV Leiden mutation, a major genetic risk factor for venous thrombosis (VT), we measured genome-wide DNA methylation levels in peripheral blood samples of 98 VT patients carrying the mutation and 251 VT patients without the mutation using the dedicated Illumina HumanMethylation450 array. The genome-wide analysis of 388,120 CpG probes identified three sites mapping to the SLC19A2 locus whose DNA methylation levels differed significantly (p0.05). In conclusion, our work clearly illustrates some promises and pitfalls of DNA methylation investigations on peripheral blood DNA in large epidemiological cohorts. DNA methylation levels at SLC19A2 are influenced by SNPs in LD with FV Leiden, but these DNA methylation marks do not explain the incomplete penetrance of the FV Leiden mutation.
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- 2014
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4. Thrombin Generation Potential and Whole-Blood DNA methylation
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Ares Rocanin-Arjo, Pierre-Emmanuel Morange, Jessica Dennis, Pierre Suchon, Vinh Truong, Dylan Aïssi, and David-Alexandre Trégouët
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business.industry ,Thrombin ,DNA ,Hematology ,DNA Methylation ,Biology ,Thrombin generation ,DNA metabolism ,Text mining ,Biochemistry ,DNA methylation ,Humans ,business ,Blood Coagulation ,Whole blood - Published
- 2015
5. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration
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Riccardo E. Marioni, Christopher J. O'Donnell, Oscar H. Franco, Johan G. Eriksson, Francesco Cucca, Jonathan Marten, Alexander P. Reiner, Tim D. Spector, Philipp S. Wild, Paul Mitchell, Wolfgang Koenig, Barbara McKnight, J. Wouter Jukema, Alan F. Wright, Maria Sabater-Lleal, Charles Kooperberg, Albert Hofman, Talin Haritunians, Martina Müller-Nurasyid, Jie Huang, Jie Yao, Marcus E. Kleber, Pau Navarro, Nicholas L. Smith, Jennifer E. Huffman, Lynda M. Rose, Russell P. Tracy, Antti-Pekka Sarin, Stefania Bandinelli, Ian J. Deary, Aarno Palotie, Saonli Basu, Caroline Hayward, Kent D. Taylor, Winfried März, Aaron R. Folsom, Anne Grotevendt, Lawrence F. Bielak, Tarunveer S. Ahluwalia, Ming-Huei Chen, Alexander Teumer, Graciela E. Delgado, Sharon L.R. Kardia, Peter K. Joshi, Wendy L. McArdle, Toshiko Tanaka, Jing Hua Zhao, Diane M. Becker, Pierre-Emmanuel Morange, Alanna C. Morrison, Annette Kifley, Igor Rudan, Lorna M. Lopez, Kay-Tee Khaw, Nicholas J. Wareham, Eco J. C. de Geus, Mohsen Ghanbari, Jari Lahti, Tatijana Zemunik, John M. Starr, Magdalena Zoledziewska, Anuj Goel, Dena G. Hernandez, Abbas Dehghan, Ozren Polasek, Melanie Waldenberger, Helene Riess, Rodney J. Scott, Qiong Yang, Robert A. Scott, Nancy S. Jenny, Johanna Mazur, Weihong Tang, Paul M. Ridker, Torben Hansen, Anders Hamsten, James F. Wilson, Jouke J. Hottenga, Cristina Venturini, Paul L. Auer, Geoffrey H. Tofler, Pirro G. Hysi, Mark G. Mcevoy, Ann Rumley, Fernando Rivadeneira, Naveed Sattar, Ivana Kolcic, Jie Jin Wang, Jingmin Liu, Stella Trompet, Elizabeth G. Holliday, Sarah H. Wild, Maristella Steri, Uwe Völker, Tanja Zeller, Patricia A. Peyser, P. Eline Slagboom, Massimo Mangino, André G. Uitterlinden, Paul S. de Vries, Dorret I. Boomsma, Harry Campbell, Vera Grossmann, Gonneke Willemsen, Katri Räikkönen, Edoardo Fiorillo, Ares Rocanin-Arjo, Gordon D.O. Lowe, David P. Strachan, Anton J. M. de Craen, Moniek P.M. de Maat, David-Alexandre Trégouët, Jennifer A. Brody, Rehan Qayyum, Lisa R. Yanek, Luigi Ferrucci, Andreas Greinacher, Lewis C. Becker, Hugh Watkins, David J. Stott, Min A. Jhun, Tina L. Berentzen, Annette Peters, Bengt Sennblad, Daniel I. Chasman, Lihong Qi, Christopher Oldmeadow, Harald Binder, Xiuqing Guo, John Attia, Bruce M. Psaty, 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), Biological Psychology, EMGO+ - Quality of Care, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidemiology, Hematology, and Internal Medicine
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Adult ,Male ,0301 basic medicine ,Netherlands Twin Register (NTR) ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,White People ,03 medical and health sciences ,INDEL Mutation ,Genetics ,Humans ,1000 Genomes Project ,International HapMap Project ,Indel ,Molecular Biology ,Genetics (clinical) ,ComputingMilieux_MISCELLANEOUS ,Aged ,Genetic association ,Aged, 80 and over ,Association Studies Articles ,Fibrinogen ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,General Medicine ,Middle Aged ,Genetic architecture ,030104 developmental biology ,Genetic Loci ,Female ,GENOME-WIDE ASSOCIATION ,C-REACTIVE PROTEIN ,CARDIOVASCULAR-DISEASE ,CIRCULATING FIBRINOGEN ,GENETIC ARCHITECTURE ,VARIANTS ,DESIGN ,HEMOSTASIS ,RESOURCE ,HEALTH ,Imputation (genetics) ,Genome-Wide Association Study - Abstract
Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including similar to 120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci ; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
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- 2016
6. Runs of Homozygosity: Association with Coronary Artery Disease and Gene Expression in Monocytes and Macrophages
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Alison H. Goodall, Muredach P. Reilly, François Cambien, Radoslaw Debiec, Nilesh J. Samani, Inke R. König, Paraskevi Christofidou, Christian Hengstenberg, Ruth McPherson, Peter S. Braund, Christopher P. Nelson, Robert Roberts, John R. Thompson, Ares Rocanin Arjo, Maciej Tomaszewski, Majid Nikpay, Christina Loley, Fadi J. Charchar, Willem H. Ouwehand, David-Alexandre Trégouët, Mingyao Li, Heribert Schunkert, Jeanette Erdmann, Liming Qu, and Matthew Denniff
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Genes, Recessive ,Coronary Artery Disease ,Biology ,Runs of Homozygosity ,Article ,Monocytes ,White People ,Pathogenesis ,Coronary artery disease ,Gene expression ,Genetics ,medicine ,Humans ,Genetics(clinical) ,RNA, Messenger ,Gene ,Genetics (clinical) ,Regulation of gene expression ,Monocyte ,Macrophages ,Homozygote ,Age Factors ,Control subjects ,medicine.disease ,medicine.anatomical_structure ,Gene Expression Regulation ,Immunology - Abstract
Runs of homozygosity (ROHs) are recognized signature of recessive inheritance. Contributions of ROHs to the genetic architecture of coronary artery disease and regulation of gene expression in cells relevant to atherosclerosis are not known. Our combined analysis of 24,320 individuals from 11 populations of white European ethnicity showed an association between coronary artery disease and both the count and the size of ROHs. Individuals with coronary artery disease had approximately 0.63 (95% CI: 0.4-0.8) excess of ROHs when compared to coronary-artery-disease-free control subjects (p = 1.49 × 10(-9)). The average total length of ROHs was approximately 1,046.92 (95% CI: 634.4-1,459.5) kb greater in individuals with coronary artery disease than control subjects (p = 6.61 × 10(-7)). None of the identified individual ROHs was associated with coronary artery disease after correction for multiple testing. However, in aggregate burden analysis, ROHs favoring increased risk of coronary artery disease were much more common than those showing the opposite direction of association with coronary artery disease (p = 2.69 × 10(-33)). Individual ROHs showed significant associations with monocyte and macrophage expression of genes in their close proximity-subjects with several individual ROHs showed significant differences in the expression of 44 mRNAs in monocytes and 17 mRNAs in macrophages when compared to subjects without those ROHs. This study provides evidence for an excess of homozygosity in coronary artery disease in outbred populations and suggest the potential biological relevance of ROHs in cells of importance to the pathogenesis of atherosclerosis.
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- 2015
7. Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism
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Christophe Tzourio, Lasse Folkersen, Marieke C H De Visser, Sara Lindström, Ramin Monajemi, Noémie Saut, David M. Smadja, Antonio Fabio Di Narzo, Jean-François Dartigues, Paul M. Ridker, Marine Germain, Mete Civelek, Nicholas L. Smith, François Cambien, Ares Rocanin-Arjo, Christopher Kabrhel, Alison H. Goodall, Aaron R. Folsom, Pieter H. Reitsma, Saonli Basu, Eline Slagboom, Lu-Chen Weng, Kent D. Taylor, Hugoline G. de Haan, Jeanine Houwing-Duitermaat, Peter Kraft, Panos Deloukas, Christopher P. Nelson, Claudine Berr, Lynda M. Rose, Ke Hao, Bruce M. Psaty, Nilesh J. Samani, Jennifer A. Brody, Pierre Suchon, Philippe Amouyel, Jean-François Deleuze, Kerri L. Wiggins, Grégoire Le Gal, Daniel I. Chasman, John A. Heit, Dylan Aïssi, Astrid van Hylckama Vlieg, Pierre-Emmanuel Morange, Mariza de Andrade, Weihong Tang, Frits R. Rosendaal, David-Alexandre Trégouët, Per Eriksson, 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), Brigham and Women's Hospital [Boston], Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Program in Genetic Epidemiology and Statistical Genetics (PGESG - BOSTON), Harvard School of Public Health, Mayo Clinic (MC), Division of Biomedical Statistics and Informatics, Mayo Clinic, Einthoven Laboratory for Experimental Vascular Medicine (ELEVM - LEIDEN), Department of Epidemiology, University of Washington [Seattle], 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), Laboratoire d'hématologie, Assistance Publique - Hôpitaux de Marseille (APHM), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'angiologie et d'hémostase (MR), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM), NIHR Leicester Cardiovascular Biomedical Research Unit, University of Leicester, Department of Cardiovascular Sciences [Leicester], Department of PharmacoGenetics (DPG - COPENHAGEN), NOVO NORDISK PARK, Department of Medical Statistics and Bioinformatics, Harvard Medical School [Boston] (HMS), Section Molecular Epidemiology, Leiden University Medical Center (LUMC), Division of epidemiology, Dalla Lana School of Public Health, University of Toronto, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, William Harvey Research Institute, Barts and the London Medical School, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Los Angeles Biomedical Research Institute and Department of Pediatrics (LA Biomed Res Institute), Harbor UCLA Medical Center [Torrance, Ca.], Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Atherosclerosis Research Unit, Karolinska Institutet [Stockholm]-Department of Medicine Solna-Cardiovascular Genetics Group, Group Health Research Institute, Group Health Cooperative, Université de Lille, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Division of Biostatistics (Biostat - MINNEAPOLIS), University of Minnesota System-University of Minnesota System, Department of Emergency Medicine, Massachusetts General Hospital [Boston], Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Seattle Epidemiologic Research and Information Center of the Department of Veterans Affairs Office of Research and Development, Fibrinolyse et Pathologie Vasculaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Universitaire de Genève, Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP], Division of Epidemiology & Community Health, Univ of Minnesota, Minneapolis , MN, Program in Genetic Epidemiology and Statistical Genetics ( PGESG - BOSTON ), Mayo Clinic ( MC ), Einthoven Laboratory for Experimental Vascular Medicine ( ELEVM - LEIDEN ), 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 ), Assistance Publique - Hôpitaux de Marseille ( APHM ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Innovations thérapeutiques en hémostase ( IThEM - U1140 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Investigation Clinique ( CIC - Brest ), Université de Brest ( UBO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'angiologie et d'hémostase ( MR ), Groupe d'Etude de la Thrombose de Bretagne Occidentale ( GETBO ), Université de Brest ( UBO ), Mount Sinai School of Medicine, Department of PharmacoGenetics ( DPG - COPENHAGEN ), Division of Preventive Medicine, Department of Medicine, Brigham and Women ’ s Hospital, Harvard Medical School, Boston, MA, USA, Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA, Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Neuropsychiatrie : recherche épidémiologique et clinique, Université Montpellier 1 ( UM1 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Los Angeles Biomedical Research Institute and Department of Pediatrics ( LA Biomed Res Institute ), Harbor UCLA Medical Center 1000 W Carson Street, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ), Division of Biostatistics ( Biostat - MINNEAPOLIS ), University of Minnesota [Minneapolis], Massachusetts General Hospital, Harvard Medical School, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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], University of Minnesota [Twin Cities], Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), and Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
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Genotype ,Tetraspanins ,[SDV]Life Sciences [q-bio] ,Genome-wide association study ,Single-nucleotide polymorphism ,Disease ,030204 cardiovascular system & hematology ,Lung injury ,Biology ,Bioinformatics ,Article ,03 medical and health sciences ,0302 clinical medicine ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,[ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology ,Genetics ,Odds Ratio ,SNP ,Humans ,Genetics(clinical) ,Genetic Predisposition to Disease ,cardiovascular diseases ,Genetics (clinical) ,030304 developmental biology ,Genetic association ,0303 health sciences ,Membrane Glycoproteins ,[ SDV ] Life Sciences [q-bio] ,Membrane Transport Proteins ,Odds ratio ,Venous Thromboembolism ,[ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,equipment and supplies ,3. Good health ,Meta-analysis ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Genome-Wide Association Study - Abstract
International audience; Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10(-8) including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10(-16)) and 1.21 (p = 2.75 × 10(-15)), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.
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- 2015
8. A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential
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David-Alexandre Trégouët, Anne-Marie Dupuy, Noémie Saut, Marine Germain, Martine Alhenc-Gelas, Corinne Frere, Luc Letenneur, Philipp S. Wild, Alison H. Goodall, Ares Rocanin-Arjo, Philippe Amouyel, Pierre-Emmanuel Morange, Marie-Christine Alessi, Laure Carcaillon, Marion Bertrand, William Cohen, François Cambien, Tanja Zeller, and Pierre-Yves Scarabin
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Genetics ,Adult ,Male ,Immunology ,Thrombin ,Genome-wide association study ,Cell Biology ,Hematology ,Orosomucoid ,Biology ,Middle Aged ,Biochemistry ,Thrombin generation ,Polymorphism, Single Nucleotide ,Novel gene ,Meta-analysis ,medicine ,Humans ,Female ,Blood Coagulation Tests ,Gene ,circulatory and respiratory physiology ,medicine.drug ,Genome-Wide Association Study - Abstract
Thrombin, the major enzyme of the hemostatic system, is involved in biological processes associated with several human diseases. The capacity of a given individual to generate thrombin, called the thrombin generation potential (TGP), can be robustly measured in plasma and was shown to associate with thrombotic disorders. To investigate the genetic architecture underlying the interindividual TGP variability, we conducted a genome-wide association study in 2 discovery samples (N = 1967) phenotyped for 3 TGP biomarkers, the endogenous thrombin potential, the peak height, and the lag time, and replicated the main findings in 2 independent studies (N = 1254). We identified the ORM1 gene, coding for orosomucoid, as a novel locus associated with lag time variability, reflecting the initiation process of thrombin generation with a combined P value of P = 7.1 × 10(-15) for the lead single nucleotide polymorphism (SNP) (rs150611042). This SNP was also observed to associate with ORM1 expression in monocytes (P = 8.7 × 10(-10)) and macrophages (P = 3.2 × 10(-3)). In vitro functional experiments further demonstrated that supplementing normal plasma with increasing orosomucoid concentrations was associated with impaired thrombin generation. These results pave the way for novel mechanistic pathways and therapeutic perspectives in the etiology of thrombin-related disorders.
- Published
- 2013
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