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1. The Assistance Publique Hôpitaux de Marseille’s Biobank

Author

Etienne Dougy, Dominique Figarella-Branger, Pierre-Emmanuel Morange, Annachiara De Sandre-Giovannoli, Bruno Lacarelle, Karine Bertaux, Karine Pedeillier, Noémie Saut, Carine Jiguet-Jiglaire, Soutsakhone Tong, and Karine Achache

Subjects
certified quality management system, neoplasm, rare genetic diseases, hematological diseases, cardiovascular diseases, Medicine, Computer applications to medicine. Medical informatics, R858-859.7
Abstract

The biobank of the Assistance Publique Hôpitaux de Marseille (AP-HM) works as a multi-site biobank around one Quality Management System. The biobank works on the collection, preparation, storage and release of biological resources and their associated data. It receives tissue samples for neoplasms, DNA and cells for rare genetic diseases and blood samples for hematological and cardiovascular diseases. These samples are provided and classified by experts of different domains; the samples are under strict technical protocols with appropriate clinical data. This wide range of sample types, diseases and services allows collaborations with public or private laboratories to customize research projects or therapeutic trials. Funding statement: The AP-HM biobank is supported by the French government’s MIG grant, intended to cover part of its annual cost based on its annual activity, valorization of released samples and funds from the AP-HM.

Published
2020
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2. Macrothrombocytopenia and dense granule deficiency associated with FLI1 variants: ultrastructural and pathogenic features

Author

Paul Saultier, Léa Vidal, Matthias Canault, Denis Bernot, Céline Falaise, Catherine Pouymayou, Jean-Claude Bordet, Noémie Saut, Agathe Rostan, Véronique Baccini, Franck Peiretti, Marie Favier, Pauline Lucca, Jean-François Deleuze, Robert Olaso, Anne Boland, Pierre Emmanuel Morange, Christian Gachet, Fabrice Malergue, Sixtine Fauré, Anita Eckly, David-Alexandre Trégouët, Marjorie Poggi, and Marie-Christine Alessi

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Congenital macrothrombocytopenia is a family of rare diseases, of which a significant fraction remains to be genetically characterized. To analyze cases of unexplained thrombocytopenia, 27 individuals from a patient cohort of the Bleeding and Thrombosis Exploration Center of the University Hospital of Marseille were recruited for a high-throughput gene sequencing study. This strategy led to the identification of two novel FLI1 variants (c.1010G>A and c.1033A>G) responsible for macrothrombocytopenia. The FLI1 variant carriers’ platelets exhibited a defect in aggregation induced by low-dose adenosine diphosphate (ADP), collagen and thrombin receptor-activating peptide (TRAP), a defect in adenosine triphosphate (ATP) secretion, a reduced mepacrine uptake and release and a reduced CD63 expression upon TRAP stimulation. Precise ultrastructural analysis of platelet content was performed using transmission electron microscopy and focused ion beam scanning electron microscopy. Remarkably, dense granules were nearly absent in the carriers’ platelets, presumably due to a biogenesis defect. Additionally, 25–29% of the platelets displayed giant α-granules, while a smaller proportion displayed vacuoles (7–9%) and autophagosome-like structures (0–3%). In vitro study of megakaryocytes derived from circulating CD34+ cells of the carriers revealed a maturation defect and reduced proplatelet formation potential. The study of the FLI1 variants revealed a significant reduction in protein nuclear accumulation and transcriptional activity properties. Intraplatelet flow cytometry efficiently detected the biomarker MYH10 in FLI1 variant carriers. Overall, this study provides new insights into the phenotype, pathophysiology and diagnosis of FLI1 variant-associated thrombocytopenia.

Published
2017
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3. Germline variants in ETV6 underlie reduced platelet formation, platelet dysfunction and increased levels of circulating CD34+ progenitors

Author

Marjorie Poggi, Matthias Canault, Marie Favier, Ernest Turro, Paul Saultier, Dorsaf Ghalloussi, Veronique Baccini, Lea Vidal, Anna Mezzapesa, Nadjim Chelghoum, Badreddine Mohand-Oumoussa, Céline Falaise, Rémi Favier, Willem H. Ouwehand, Mathieu Fiore, Franck Peiretti, Pierre Emmanuel Morange, Noémie Saut, Denis Bernot, Andreas Greinacher, NIHR BioResource, Alan T. Nurden, Paquita Nurden, Kathleen Freson, David-Alexandre Trégouët, Hana Raslova, and Marie-Christine Alessi

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Variants in ETV6, which encodes a transcription repressor of the E26 transformation-specific family, have recently been reported to be responsible for inherited thrombocytopenia and hematologic malignancy. We sequenced the DNA from cases with unexplained dominant thrombocytopenia and identified six likely pathogenic variants in ETV6, of which five are novel. We observed low repressive activity of all tested ETV6 variants, and variants located in the E26 transformation-specific binding domain (encoding p.A377T, p.Y401N) led to reduced binding to corepressors. We also observed a large expansion of megakaryocyte colony-forming units derived from variant carriers and reduced proplatelet formation with abnormal cytoskeletal organization. The defect in proplatelet formation was also observed in control CD34+ cell-derived megakaryocytes transduced with lentiviral particles encoding mutant ETV6. Reduced expression levels of key regulators of the actin cytoskeleton CDC42 and RHOA were measured. Moreover, changes in the actin structures are typically accompanied by a rounder platelet shape with a highly heterogeneous size, decreased platelet arachidonic response, and spreading and retarded clot retraction in ETV6 deficient platelets. Elevated numbers of circulating CD34+ cells were found in p.P214L and p.Y401N carriers, and two patients from different families suffered from refractory anemia with excess blasts, while one patient from a third family was successfully treated for acute myeloid leukemia. Overall, our study provides novel insights into the role of ETV6 as a driver of cytoskeletal regulatory gene expression during platelet production, and the impact of variants resulting in platelets with altered size, shape and function and potentially also in changes in circulating progenitor levels.

Published
2017
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4. Caution in interpreting results from imputation analysis when linkage disequilibrium extends over a large distance: a case study on venous thrombosis.

Author

Marine Germain, Noémie Saut, Tiphaine Oudot-Mellakh, Luc Letenneur, Anne-Marie Dupuy, Marion Bertrand, Marie-Christine Alessi, Jean-Charles Lambert, Diana Zelenika, Joseph Emmerich, Laurence Tiret, Francois Cambien, Mark Lathrop, Philippe Amouyel, Pierre-Emmanuel Morange, and David-Alexandre Trégouët

Subjects
Medicine, Science
Abstract

By applying an imputation strategy based on the 1000 Genomes project to two genome-wide association studies (GWAS), we detected a susceptibility locus for venous thrombosis on chromosome 11p11.2 that was missed by previous GWAS analyses that had been conducted on the same datasets. A comprehensive linkage disequilibrium and haplotype analysis of the whole locus where twelve SNPs exhibited association p-values lower than 2.23 10(-11) and the use of independent case-control samples demonstrated that the culprit variant was a rare variant located ~1 Mb away from the original hits, not tagged by current genome-wide genotyping arrays and even not well imputed in the original GWAS samples. This variant was in fact the rs1799963, also known as the FII G20210A prothrombin mutation. This work may be of major interest not only for its scientific impact but also for its methodological findings.

Published
2012
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5. Genetics of venous thrombosis: insights from a new genome wide association study.

Author

Marine Germain, Noémie Saut, Nicolas Greliche, Christian Dina, Jean-Charles Lambert, Claire Perret, William Cohen, Tiphaine Oudot-Mellakh, Guillemette Antoni, Marie-Christine Alessi, Diana Zelenika, François Cambien, Laurence Tiret, Marion Bertrand, Anne-Marie Dupuy, Luc Letenneur, Mark Lathrop, Joseph Emmerich, Philippe Amouyel, David-Alexandre Trégouët, and Pierre-Emmanuel Morange

Subjects
Medicine, Science
Abstract

BACKGROUND: Venous Thrombosis (VT) is a common multifactorial disease associated with a major public health burden. Genetics factors are known to contribute to the susceptibility of the disease but how many genes are involved and their contribution to VT risk still remain obscure. We aimed to identify genetic variants associated with VT risk. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a genome-wide association study (GWAS) based on 551,141 SNPs genotyped in 1,542 cases and 1,110 controls. Twelve SNPs reached the genome-wide significance level of 2.0×10(-8) and encompassed four known VT-associated loci, ABO, F5, F11 and FGG. By means of haplotype analyses, we also provided novel arguments in favor of a role of HIVEP1, PROCR and STAB2, three loci recently hypothesized to participate in the susceptibility to VT. However, no novel VT-associated loci came out of our GWAS. Using a recently proposed statistical methodology, we also showed that common variants could explain about 35% of the genetic variance underlying VT susceptibility among which 3% could be attributable to the main identified VT loci. This analysis additionally suggested that the common variants left to be identified are not uniformly distributed across the genome and that chromosome 20, itself, could contribute to ∼7% of the total genetic variance. CONCLUSIONS/SIGNIFICANCE: This study might also provide a valuable source of information to expand our understanding of biological mechanisms regulating quantitative biomarkers for VT.

Published
2011
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6. GATA1 pathogenic variants disrupt MYH10 silencing during megakaryopoiesis

Author

Timothée Bigot, Marie Loosveld, Noémie Saut, Paul Saultier, Céline Falaise, Pierre-Emmanuel Morange, Sandrine Cabantous, Franck Peiretti, Johannes van Agthoven, Jean-Claude Bordet, Denis Bernot, Delphine Potier, Dominique Payet-Bornet, Matthias Canault, Michel Pucéat, Marie-Christine Alessi, Marjorie Poggi, 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), Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), AUTRES, Massachusetts General Hospital [Boston], Harward Medical School, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), and DUMENIL, Anita

Subjects
Blood Platelets, [SDV]Life Sciences [q-bio], MYH10, Biology, Thrombopoiesis, 03 medical and health sciences, 0302 clinical medicine, Transcription (biology), GATA1, Gene expression, Gene silencing, Humans, GATA1 Transcription Factor, Gene Silencing, Transcription factor, Gene, 030304 developmental biology, Zinc finger, Genetics, 0303 health sciences, Nonmuscle Myosin Type IIB, Myosin Heavy Chains, Intron, Hematology, Thrombocytopenia, 3. Good health, [SDV] Life Sciences [q-bio], functional variants, platelets, downstream targets, Megakaryocytes, 030215 immunology, Transcription Factors
Abstract

International audience; BackgroundGATA1 is an essential transcription factor for both polyploidization and megakaryocyte (MK) differentiation. The polyploidization defect observed in GATA1 variant carriers is not well understood.ObjectiveTo extensively phenotype two pedigrees displaying different variants in the GATA1 gene and determine if GATA1 controls MYH10 expression levels, a key modulator of MK polyploidization.MethodA total of 146 unrelated propositi with constitutional thrombocytopenia were screened on a multigene panel. We described the genotype-phenotype correlation in GATA1 variant carriers and investigated the effect of these novel variants on MYH10 transcription using luciferase constructs.ResultsThe clinical profile associated with the p.L268M variant localized in the C terminal zinc finger was unusual in that the patient displayed bleeding and severe platelet aggregation defects without early-onset thrombocytopenia. p.N206I localized in the N terminal zinc finger was associated, on the other hand, with severe thrombocytopenia (15G/L) in early life. High MYH10 levels were evidenced in platelets of GATA1 variant carriers. Analysis of MKs anti-GATA1 chromatin immunoprecipitation-sequencing data revealed two GATA1 binding sites, located in the 3′ untranslated region and in intron 8 of the MYH10 gene. Luciferase reporter assays showed their respective role in the regulation of MYH10 gene expression. Both GATA1 variants significantly alter intron 8 driven MYH10 transcription.ConclusionThe discovery of an association between MYH10 and GATA1 is a novel one. Overall, this study suggests that impaired MYH10 silencing via an intronic regulatory element is the most likely cause of GATA1-related polyploidization defect.

Published
2021

7. GATA1 pathogenic variants disrupt MYH10 silencing during megakaryopoiesis

Author

Marie Loosveld, Céline Falaise, Matthias Canault, Noémie Saut, Marjorie Poggi, Paul Saultier, Pierre Morange, Marie-Christine Alessi, Michel Pucéat, Franck Peiretti, J Von Agthoven, Sandrine Cabantous, Denis Bernot, and JC Bordet

Subjects
MYH10, Gene silencing, GATA1, Biology, Cell biology, Megakaryopoiesis
Published
2021

8. ABO blood group, glycosyltransferase activity and risk of Venous Thrombosis

Author

Pierre-Emmanuel Morange, Jacques Chiaroni, Pascal Bailly, Noémie Saut, Manal Ibrahim Kosta, David-Alexandre Trégouët, Pierre Suchon, Louisa Goumidi, and Monique Silvy

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, biology, Chemistry, Plasma levels, medicine.disease, Glycosyltransferase activity, Venous thrombosis, chemistry.chemical_compound, Endocrinology, Von Willebrand factor, hemic and lymphatic diseases, Internal medicine, Galactose, AGT activity, ABO blood group system, parasitic diseases, Glycosyltransferase, biology.protein, medicine
Abstract

IntroductionABO blood group influence the risk of venous thrombosis (VT) by modifying A and B glycosyltransferases (AGT and BGT) activities that further modulates Factor VIII (FVIII) and von Willebrand Factor (VWF) plasma levels. The aim of this work was to evaluate the association of plasma GTs activities with VWF/FVIII plasma levels and VT risk in a case-control study.Materials and Methods420 cases were matched with 420 controls for age and ABO blood group. GT activities in plasma were measured using the quantitative transfer of tritiated N-acetylgalactosamine or galactose to the 2’-fucosyl-lactose and expressed in disintegration per minute/30µL of plasma and 2 hours of reaction (dpm/30µL/2H). FVIII and VWF plasma levels were respectively measured using human FVIII-deficient plasma in a 1-stage factor assay and STA LIATEST VWF (Diagnostica Stago).ResultsA and B GT activities were significantly lower in cases than in controls (8119±4027 vs 9682±4177 dpm/30µL/2H, p=2.03 × 10−5, and 4931±2305 vs 5524±2096 dpm/30µL/2H, p=0.043 respectively). This association was observed whatever the ABO blood groups. The ABO A1 blood group was found to explain∼80% of AGT activity. After adjusting for ABO blood groups, AGT activity was not correlated to VWF/FVIII plasma levels. Conversely, there was a moderate correlation (ρ∼0.30) between BGT activity and VWF/ FVIII plasma levels in B blood group carriers.ConclusionThis work showed, for the first time, that GT activities were decreased in VT patients in comparison to controls with the same ABO blood group. The biological mechanisms responsible for this association remained to be determined.

Published
2020

9. Bernard–Soulier syndrome: first human case due to a homozygous deletion of GP9 gene

Author

Florentine Garaix, Dorsaf Ghalloussi, Michel Tsimaratos, Caroline Rousset‐Rouvière, Noémie Saut, Marie-Christine Alessi, Hervé Chambost, Paul Saultier, Véronique Baccini, Cornel Popovici, 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), Hôpital de la Timone [CHU - APHM] (TIMONE), 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), Service de pédiatrie, d'hématologie et d'oncologie [Hôpital de La Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), and Prémilleux, Annick

Subjects
Male, Platelet aggregation, [SDV]Life Sciences [q-bio], Platelet disorder, thrombocytopenia, platelet membrane, Biology, platelet genetic diseases, Bernard–Soulier syndrome, 03 medical and health sciences, 0302 clinical medicine, Bone Marrow, medicine, Humans, platelet disorders, Gene, Sequence Deletion, 030304 developmental biology, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Infant, Newborn, Bernard-Soulier Syndrome, Hematology, medicine.disease, Pedigree, 3. Good health, [SDV] Life Sciences [q-bio], Platelet Glycoprotein GPIb-IX Complex, platelet aggregation, Immunology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract

International audience; Bernard–Soulier Syndrome (BSS) is a rare (1:1 million) hereditary bleeding disorder caused by defects in the platelet glycoprotein (GP)‐Ib/IX/V complex, a receptor for von Willebrand factor (VWF) and thrombin (Lanza, 2006; Berndt & Andrews, 2011). Patients typically present with epistaxis, petechial or gingival bleeding with onset already in infancy. They present with macrothrombocytopenia and their platelets do not agglutinate in response to ristocetin, while maintaining a normal aggregation in response to a variety of aggregating agents. GPIb/IX/V complex consists of two GPIbα and four GPIbβ subunits stabilized by disulphide bonds (Luo et al., 2007). This heterodimer is non‐covalently associated with two GPIX and one GPV subunits. The N‐terminal residues of GPIbα form seven leucine‐rich repeats (LRRs) and include the binding sites for VWF and thrombin. BSS is due to biallelic loss‐of‐function pathogenic variants (deletions, insertions and nonsense mutations) in GPIBA, GPIBB or GP9 genes encoding GPIb/IX/V complex (Savoia et al., 2014). However, so far, no mutation in GP5 causing BSS has been reported yet. Most of the mutations prevent the formation of the complex or trafficking it through the endoplasmic reticulum and Golgi apparatus and alter receptor expression (Salles et al., 2008; Savoia et al., 2011; Nurden et al., 2012).

Published
2020

10. Common Risk Factors Add to Inherited Thrombophilia to Predict Venous Thromboembolism Risk in Families

Author

Dominique Brunet, Noémie Resseguier, Noémie Saut, M. C. Barthet, Manal Ibrahim, David A. Tregouet, Alexia Robin, Geoffroy Venton, Pierre Suchon, Pierre Morange, Marie-Christine Alessi, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix Marseille Université (AMU), 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), Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB), Program Hospitalier de Recherche Clinique [PHRC 2003], and Centre recherche en CardioVasculaire et Nutrition (C2VN)

Subjects
lcsh:Diseases of the circulatory (Cardiovascular) system, Pediatrics, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Population, venous thromboembolism, Single-nucleotide polymorphism, 030204 cardiovascular system & hematology, Thrombophilia, 03 medical and health sciences, 0302 clinical medicine, single nucleotide polymorphism, ABO blood group system, Medicine, 030212 general & internal medicine, cardiovascular diseases, education, thrombophilia, 2. Zero hunger, education.field_of_study, Framingham Risk Score, family medical history, business.industry, Incidence (epidemiology), risk assessment, medicine.disease, equipment and supplies, 3. Good health, lcsh:RC666-701, Original Article, business, Risk assessment, Body mass index
Abstract

International audience; The clinical venous thromboembolism (VTE) pattern often shows wide heterogeneity within relatives of a VTE-affected family, although they carry the same thrombophilia defect. It is then mandatory to develop additional tools for assessing VTE risk in families with thrombophilia. This study aims to assess whether common environmental and genetic risk factors for VTE contribute to explain this heterogeneity. A total of 2,214 relatives from 651 families with known inherited thrombophilia were recruited at the referral center for thrombophilia in Marseilles, France, from 1986 to 2013. A thrombophilia screening was systematically performed in all included relatives. According to the severity of the thrombophilia defect, individuals were split into three groups: no familial defect, mild thrombophilia, and severe thrombophilia. In addition, common genetic factors (ABO blood group and 11 polymorphisms selected on the basis of their association with VTE in the general population) were genotyped. Furthermore, body mass index and smoking were collected. VTE incidence was 1.74, 3.64, and 6.40 per 1,000 person-years in individuals with no familial defect, mild thrombophilia, and severe thrombophilia, respectively. Five common risk factors were associated with VTE in this population: obesity, smoking, ABO blood group, and F11_rs2036914 and FGG_rs2066865 polymorphisms. These common factors were then included into a three-level risk score. The score was highly efficient for assessing VTE risk in mild thrombophilia patients by identifying two groups with different VTE risk; individuals with low score had the same risk as individuals with no familial defect whereas individuals with high score had the same risk as individuals with severe thrombophilia. An overall score including the five items plus the thrombophilia status was built and displayed an area under the receiver operating characteristic curve of 0.702 for discriminating VTE and non-VTE relatives. In conclusion, integrating common environmental and genetic risk factors improved VTE risk assessment in relatives from families with thrombophilia. Ã Equally contributed to the article.

Published
2019

11. A Genome Wide Association Study on plasma FV levels identified PLXDC2 as a new modifier of the coagulation process

Author

Jean-François Deleuze, Pierre-Emmanuel Morange, Florian Thibord, Manal Ibrahim-Kosta, Per Eriksson, Lise M Hardy, Noémie Saut, Mete Civelek, Anne-Sophie Pulcrano-Nicolas, Louisa Goumidi, David-Alexandre Trégouët, Wilfried Le Goff, Sorbonne Université (SU), Université de Bordeaux (UB), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Virginia, Karolinska Institutet [Stockholm], University Hospital, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fondation Jean Dausset, Assistance Publique - Hôpitaux de Marseille (APHM), ANR-10-LABX-0013, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), 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], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Adult, Male, Cell type, In silico, Receptors, Cell Surface, Locus (genetics), Genome-wide association study, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, computational biology, Cell Line, Tumor, Genetic variation, Gene expression, Humans, genetics, coagulation factor, Blood Coagulation, Aged, Genetics, factor V, biology, Factor V, biomarkers, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Middle Aged, 3. Good health, Phenotype, Gene Expression Regulation, Factor X, Hepatocytes, biology.protein, Female, Prothrombin, Genome-Wide Association Study
Abstract

International audience; Background Factor V (FV) is a circulating protein primarily synthesized in the liver, and mainly present in plasma. It is a major component of the coagulation process. Objective To detect novel genetic loci participating to the regulation of FV plasma levels. Methods We conducted the first Genome Wide Association Study on FV plasma levels in a sample of 510 individuals and replicated the main findings in an independent sample of 1156 individuals. Results In addition to genetic variations at the F5 locus, we identified novel associations at the PLXDC2 locus, with the lead PLXDC2 rs927826 polymorphism explaining ~3.7% (P = 7.5 × 10−15 in the combined discovery and replication samples) of the variability of FV plasma levels. In silico transcriptomic analyses in various cell types confirmed that PLXDC2 expression is positively correlated to F5 expression. SiRNA experiments in human hepatocellular carcinoma cell line confirmed the role of PLXDC2 in modulating factor F5 gene expression, and revealed further influences on F2 and F10 expressions. Conclusion Our study identified PLXDC2 as a new molecular player of the coagulation process.

Published
2019

12. Minor allele of the factor V K858R variant protects from venous thrombosis only in non-carriers of factor V Leiden mutation

Author

Céline Derbois, Noémie Saut, Philippe Amouyel, Stéphanie Debette, Louisa Goumidi, Elisabetta Castoldi, Manal Ibrahim-Kosta, David M. Smadja, Marine Germain, P. van Doorn, Pierre Morange, Etienne Patin, Marie-Christine Alessi, Pierre Suchon, Robert Olaso, David A. Tregouet, Francis Couturaud, Jean-François Deleuze, Florian Thibord, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), 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 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), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie biologique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), 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), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre National de Recherche en Génomique Humaine (CNRGH), Maastricht University [Maastricht], Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, The authors would like to thank three research programs managed by the National Research Agency (ANR) as part of the French Investment for the Future initiative genetic investigations: the GENMED Laboratory of Excellence on Medical Genomics (ANR-10-LABX-0013), the French Clinical Research Infrastructure Network on Venous Thrombo-Embolism (F-CRIN INNOVTE) and the ICAN Institute for Cardiometabolism and Nutrition (ANR-10-IAHU-05) who partially supported performing genetic investigations in the MARTHA GWAS, MARTHA12, EDITH and FARIVE studies. TF was financially supported by a PhD grant from the GENMED Laboratory of Excellence on Medical Genomics (ANR-10-LABX-0013). vDP was supported by grant nr. 2014-1 from the Dutch Thrombosis Foundation. The present project was supported by a grant from CSL Behring., ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-10-INBS-0003,F-CRIN,Plateforme Nationale d'Infrastructures de Recherche Clinique(2010), ANR-10-IAHU-0005,ICAN,Institut de Cardiologie-Métabolisme-Nutrition(2010), Biochemie, RS: CARIM - R1 - Thrombosis and haemostasis, RS: CARIM - R1.01 - Blood proteins & engineering, RS: Carim - B01 Blood proteins & engineering, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre recherche en CardioVasculaire et Nutrition (C2VN), Université de Brest (UBO), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), ANR: PREFI-10-LABX-13/10-LABX-0013,GENMED,Medical Genomics(2010), ANR-10-INBS-03-01/10-INBS-0003,F-CRIN,Plateforme Nationale d'Infrastructures de Recherche Clinique(2010), ANR-10-IAHU-0005/10-IAHU-0005,ICAN,ICAN(2010), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
0301 basic medicine, Male, lcsh:Medicine, Genome-wide association study, polymorphisme, PATHWAY, 0302 clinical medicine, COAGULATION-FACTOR-V, lcsh:Science, Venous Thrombosis, RISK, Multidisciplinary, biology, Factor V, DEFECTS, Venous thrombosis, Female, France, medicine.drug, medicine.medical_specialty, Heterozygote, B-DOMAIN, Médecine humaine et pathologie, Article, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Factor V Leiden, Humans, Allele, GENOME-WIDE ASSOCIATION, coagulation, facteur viii, Alleles, Genetic Association Studies, business.industry, lcsh:R, allèle, medicine.disease, GENE, Minor allele frequency, 030104 developmental biology, Endocrinology, Amino Acid Substitution, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Case-Control Studies, biology.protein, lcsh:Q, Human health and pathology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Activated protein C resistance, business, 030217 neurology & neurosurgery, Protein C, RESISTANCE, thrombose veineuse
Abstract

Factor V serves an important role in the regulation of blood coagulation. The rs6025 (R534Q) and rs4524 (K858R) polymorphisms in the F5 gene, are known to influence the risk of venous thrombosis. While the rare Q534 (factor V Leiden) allele is associated with an increased risk of venous thrombosis, the minor R858 allele is associated with a lower risk of disease. However, no study has deeply examined the cumulative impact of these two variations on venous thrombosis risk. We study the association of these polymorphisms with the risk of venous thrombosis in 4 French case-control populations comprising 3719 patients and 4086 controls. We demonstrate that the Q534 allele has a dominant effect over R858. Besides, we show that in individuals not carrying the Q534 allele, the protective effect of the R858 allele acts in a dominant mode. Thrombin generation-based normalized activated protein C sensitivity ratio was lower in the 858R/R homozygotes than in the 858K/K homozygotes (1.92 ± 1.61 vs 2.81 ± 1.57, p = 0.025). We demonstrate that the R858 allele of the F5 rs4524 variant protects from venous thrombosis only in non-carriers of the Q534 allele of the F5 rs6025. Its protective effect is mediated by reduced factor VIII levels and reduced activated protein C resistance.

Published
2019

13. Human thymopoiesis is influenced by a common genetic variant within the TCRA-TCRD locus

Author

Lluis Quintana-Murci, Marine Germain, Magnus Fontes, Antoine Toubert, Itauá Leston Araujo, David-Alexandre Trégouët, James P. Di Santo, Emmanuel Clave, Corinne Douay, Silvia Lopez-Lastra, Milena Hasan, Bruno Charbit, Noémie Saut, Breno Luiz Melo-Lima, Darragh Duffy, Cécile Alanio, Jacob Bergstedt, Alejandra Urrutia, Cameron Ross MacPherson, Yan Li, Etienne Patin, Pierre-Emmanuel Morange, Matthew L. Albert, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Alloimmunité-Autoimmunité-Transplantation (A2T), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Lund University [Lund], Genentech, Inc., Genentech, Inc. [San Francisco], Immunité Innée - Innate Immunity, 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), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), International Group for Data Analysis (IGDA), Service d'Immunologie et d'Histocompatibilité, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by the French government’s Invest in the Future Program, managed by the Agence Nationale de la Recherche (ANR, 10-LABX-69-01). I.L.A. was a recipient of the Science without Borders PhD program from Brazil Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). J.B. is a member of the Lund Center for Control of Complex Engineering Systems (LCCC) Linnaeus Center and the Excellence Center at Linköping-Lund in Information Technology (ELLIT) Excellence Center at Lund University and is supported by the ELLIIT Excellence Center. J.P.D.S., Y.L., and S.L.-L. received funding from Institut Pasteur, INSERM, the Laboratoire d’Excellence REVIVE. A.T. and E.C. received funding from ANR grant PriCelAge (ANR-14-CE14-0030-01). Genetic investigations in the MARTHA study were supported by the GENMED Laboratory of Excellence on Medical Genomics (ANR-10-LABX-0013), We thank J. Fellay, P. Scepanovic, and C. A. W. Thorball for support with genetic analysis and J.-M. Doisne, G. M. Ranson, and H. Strick-Marchand for support with humanized mouse experiments. We thank V. Asnafi, E. Macintyre, A. Cieslak, and I. André-Schmutz for helpful discussions. We also thank the Centre d’Immunologie Humaine (Institut Pasteur, Paris, France) for support., ANR-14-CE14-0030,PriCelAge,Induction de réponses cellulaires T avec l'âge avancé(2014), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle (CRT), Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunité Innée, Centre recherche en CardioVasculaire et Nutrition (C2VN), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), ANR-14-CE14-0030,PriCelAge,Induction de réponses cellulaires T avec l’âge avancé(2014), ANR: PREFI-10-LABX-13/10-LABX-0013,GENMED,Medical Genomics(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], 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], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, education.field_of_study, T-cell receptor excision circles, T cell, Population, Genome-wide association study, Locus (genetics), General Medicine, Biology, 3. Good health, Transplantation, 03 medical and health sciences, Haematopoiesis, Thymocyte, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, education
Abstract

International audience; The thymus is the primary lymphoid organ where naïve T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age- and sex-stratified healthy adults of the Milieu Intérieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function. TREC amounts decreased with age and were higher in women compared to men. In addition, a genome-wide association study revealed a common variant (rs2204985) within the T cell receptor TCRA-TCRD locus, between the DD2 and DD3 gene segments, which associated with TREC amounts. Strikingly, transplantation of human hematopoietic stem cells with the rs2204985 GG genotype into immunodeficient mice led to thymopoiesis with higher TRECs, increased thymocyte counts, and a higher TCR repertoire diversity. Our population immunology approach revealed a genetic locus that influences thymopoiesis in healthy adults, with potentially broad implications in precision medicine.

Published
2018

14. A new heterozygous mutation in GP1BA gene responsible for macrothrombocytopenia

Author

Gérard Sébahoun, Xavier Pillois, Véronique Baccini, Hana Raslova, Philippe Rameau, Denis Bernot, Marie-Christine Alessi, Noémie Saut, Dorsaf Ghalloussi, 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), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Fibrinolyse et Pathologie Vasculaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Haut-Lévêque, Université Sciences et Technologies - Bordeaux 1 (UB)-CHU Bordeaux [Bordeaux], Plateforme imagerie et cytométrie (PFIC), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Hématologie, Hôpital Nord [CHU - APHM], Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Goletto, Marie-Hélène, Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sciences et Technologies - Bordeaux 1-CHU Bordeaux [Bordeaux], Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre recherche en CardioVasculaire et Nutrition (C2VN)

Subjects
Genetics, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, GP1BA gene, Platelet disorder, Heterozygote advantage, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, 030204 cardiovascular system & hematology, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, PLATELET DISORDERS, PLATELETS, PLATELET GENETIC DISEASES, 03 medical and health sciences, 0302 clinical medicine, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation (genetic algorithm), PLATELET MEMBRANE, Platelet, MEGAKARYOCYTOPOIESIS, ComputingMilieux_MISCELLANEOUS, 030215 immunology, Heterozygous mutation, Megakaryocytopoiesis
Abstract

International audience

Published
2018

15. Economic Analysis of Thrombo inCode, a Clinical–Genetic Function for Assessing the Risk of Venous Thromboembolism

Author

J. M. Soria, J. Sala, C. Rubio-Terrés, D. Rubio-Rodríguez, P. Suchon, J. Mateo, Sara Pich, Pierre Morange, E. Salas, Noémie Saut, Alfredo Gracia, and Joan Carles Souto

Subjects
Male, very elderly, Cost-Benefit Analysis, cost benefit analysis, middle aged, Economic analysis, genetics, Original Research Article, Aged, 80 and over, predictive value, medicine.diagnostic_test, Health Policy, Venous Thromboembolism, genetic screening, General Medicine, Middle Aged, Pulmonary embolism, female, Models, Economic, Predictive value of tests, Female, Risk assessment, medicine.drug, Adult, Economics and Econometrics, medicine.medical_specialty, venous thromboembolism, Thrombophilia, Risk Assessment, Sensitivity and Specificity, Predictive Value of Tests, decision tree, Genetic predisposition, medicine, Clinical genetic, Humans, Genetic Predisposition to Disease, human, procedures, Genetic Testing, cardiovascular diseases, Intensive care medicine, Aged, Genetic testing, business.industry, statistical model, Decision Trees, Warfarin, Public Health, Environmental and Occupational Health, Genetic variants, economics, medicine.disease, equipment and supplies, Spain, Physical therapy, business, genetic predisposition, Venous thromboembolism
Abstract

Background: Patients with venous thromboembolism (VTE) commonly have an underlying genetic predisposition. However, genetic tests nowadays in use have very low sensitivity for identifying subjects at risk of VTE. Thrombo inCode® is a new genetic tool that has demonstrated very good sensitivity, thanks to very good coverage of the genetic variants that modify the function of the coagulation pathway. Objective: To conduct an economic analysis of risk assessment of VTE from the perspective of the Spanish National Health System with Thrombo inCode® (a clinical–genetic function for assessing the risk of VTE) versus the conventional/standard method used to date (factor V Leiden and prothrombin G20210A). Methods: An economic model was created from the National Health System perspective, using a decision tree in patients aged 45 years with a life expectancy of 81 years. The predictive capacity of VTE, based on identification of thrombophilia using Thrombo inCode® and using the standard method, was obtained from two case–control studies conducted in two different populations (S. PAU and MARTHA; 1,451 patients in all). Although this is not always the case, patients who were identified as suffering from thrombophilia were subject to preventive treatment of VTE with warfarin, leading to a reduction in the number of VTE events and an increased risk of severe bleeding. The health state utilities (quality-adjusted life-years [QALYs]) and costs (in 2013 EUR values) were obtained from the literature and Spanish sources. Results: On the basis of a price of EUR 180 for Thrombo inCode®, this would be the dominant option (more effective and with lower costs than the standard method) in both populations. The Monte Carlo probabilistic analyses indicate that the dominance would occur in 100 % of the simulations in both populations. The threshold price of Thrombo inCode® needed to reach the incremental cost-effectiveness ratio (ICER) generally accepted in Spain (EUR 30,000 per QALY gained) would be between EUR 3,950 (in the MARTHA population) and EUR 11,993 (in the S. PAU population). Conclusion: According to the economic model, Thrombo inCode® is the dominant option in assessing the risk of VTE, compared with the standard method currently used. © 2015, The Author(s).

Published
2015

16. Southeast asian ovalocytosis: the need for a carefull observation of red cell indices and blood smear

Author

Pierre-Antoine Moulin, Véronique Baccini, Denis Bernot, Vanessa Nivaggioni, Charlotte Grosdidier, Noémie Saut, CHU Marseille, Nutrition, obésité et risque thrombotique (NORT), and Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Erythrocyte Indices, Male, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Cytodiagnosis, Population, Usually asymptomatic, Biology, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Pregnancy, parasitic diseases, medicine, Humans, 030212 general & internal medicine, education, Band 3, education.field_of_study, Incidental Findings, Blood Cells, Hematologic Tests, RED-CELL INDICES, Pregnancy Complications, Hematologic, Elliptocytosis, Hereditary, General Medicine, Middle Aged, medicine.disease, Southeast Asian ovalocytosis, Blood smear, Ovalocytosis, biology.protein, Female, Hemoglobin
Abstract

Southeast asian ovalocytosis (SAO) is characterized by macro-ovalocytes and ovalo-stomatocytes on blood smear. SAO is common in Malaisia and Papua-New-Guinea where upwards to 40 per cent of the population is affected in some coastal region. Inherited in an autosomal dominant way, illness results from deletion of codons 400-408 in SLC4A1 gene which encodes for band 3 erythrocyte membrane protein. This deletion is responsible for an unusual erythrocyte stiffness and oval shape of the cells on blood smear. Heterozygous carriers are usually asymptomatic whereas homozygous are not viable without an intensive antenatal care. Here, we describe 4 patients diagnosed incidentally by cytogram appearance of the Advia® 2120i (Siemens) representing hemoglobin concentration according to red blood mean cellular volume (GR/VCH).

Published
2017

17. Human thymopoiesis is influenced by a common genetic variant within the

Author

Emmanuel, Clave, Itauá Leston, Araujo, Cécile, Alanio, Etienne, Patin, Jacob, Bergstedt, Alejandra, Urrutia, Silvia, Lopez-Lastra, Yan, Li, Bruno, Charbit, Cameron Ross, MacPherson, Milena, Hasan, Breno Luiz, Melo-Lima, Corinne, Douay, Noémie, Saut, Marine, Germain, David-Alexandre, Trégouët, Pierre-Emmanuel, Morange, Magnus, Fontes, Darragh, Duffy, James P, Di Santo, Lluis, Quintana-Murci, Matthew L, Albert, and Antoine, Toubert

Subjects
Adult, Male, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, Genetic Variation, Receptors, Antigen, T-Cell, gamma-delta, Mice, SCID, Thymus Gland, Middle Aged, Cohort Studies, Young Adult, Phenotype, Genetic Loci, Animals, Humans, Female, Biomarkers, Aged, Genome-Wide Association Study
Abstract

The thymus is the primary lymphoid organ where naïve T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age- and sex-stratified healthy adults of the Milieu Intérieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function. TREC amounts decreased with age and were higher in women compared to men. In addition, a genome-wide association study revealed a common variant (rs2204985) within the T cell receptor

Published
2017

18. Protein S Heerlen mutation heterozygosity is associated with venous thrombosis risk

Author

Xavier Jouven, Beata Gyorgy, Pierre-Emmanuel Morange, Marie Germain, David M. Smadja, Noémie Saut, Marie-Christine Alessi, Pierre Suchon, Aurélien Delluc, Mona Ibrahim, David-Alexandre Trégouët, Jean-François Deleuze, 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), 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), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Service d'hématologie biologique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-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), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Dpt Cardiologie [CHU Georges Pompidou], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-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) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), HAL UPMC, Gestionnaire, 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 ), 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], Université de Brest ( UBO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de la Cavale Blanche, Service d'hématologie biologique [CHU Hôpital Européen Georges Pompidou], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Innovations thérapeutiques en hémostase ( IThEM - U1140 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), and Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset

Subjects
0301 basic medicine, medicine.medical_specialty, Mutation, Missense, 030204 cardiovascular system & hematology, medicine.disease_cause, Gastroenterology, Risk Assessment, Protein S, Article, Loss of heterozygosity, 03 medical and health sciences, Plasma, 0302 clinical medicine, Polymorphism (computer science), [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Internal medicine, Genotype, medicine, Humans, Genetic Predisposition to Disease, Venous Thrombosis, Mutation, Multidisciplinary, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, PROTEIN S HEERLEN, business.industry, medicine.disease, Quantitative determination, Surgery, Venous thrombosis, 030104 developmental biology, biology.protein, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Hereditary Protein S (PS) deficiency is a rare coagulation disorder associated with an increased risk of venous thrombosis (VT). The PS Heerlen (PSH) mutation is a rare S501P mutation that was initially considered to be a neutral polymorphism. However, it has been later shown that PSH has a reduced half-life in vivo which may explain the association of PSH heterozygosity with mildly reduced levels of plasma free PS (FPS). Whether the risk of VT is increased in PSH carriers remains unknown. We analyzed the association of PSH (rs121918472 A/G) with VT in 4,173 VT patients and 5,970 healthy individuals from four independent case-control studies. Quantitative determination of FPS levels was performed in a subsample of 1257 VT patients. In the investigated populations, the AG genotype was associated with an increased VT risk of 6.57 [4.06–10.64] (p = 1.73 10−14). In VT patients in whom PS deficiency was excluded, plasma FPS levels were significantly lower in individuals with PSH when compared to those without [72 + 13 vs 91 + 21 UI/dL; p = 1.86 10−6, mean + SD for PSH carriers (n = 21) or controls (n = 1236) respectively]. We provide strong evidence that the rare PSH variant is associated with VT in unselected individuals.

Published
2017

19. Effect of CYP2C19*2 and *17 Genetic Variants on Platelet Response to Clopidogrel and Prasugrel Maintenance Dose and Relation to Bleeding Complications

Author

Charlotte Grosdidier, William Cohen, Laurence Camoin, Mathieu Pankert, Jacques Quilici, Marie-Christine Alessi, Thomas Cuisset, Jean-Louis Bonnet, Marie Loosveld, Bénédicte Gaborit, Pierre Julien Moro, Marc Lambert, Noémie Saut, Pierre-Emmanuel Morange, and Shirley Beguin

Subjects
Blood Platelets, Male, medicine.medical_specialty, Ticlopidine, Prasugrel, Genotype, Myocardial Infarction, Hemorrhage, Thiophenes, CYP2C19, Polymerase Chain Reaction, Piperazines, Risk Factors, Internal medicine, medicine, Humans, Platelet, Prospective Studies, Acute Coronary Syndrome, Prospective cohort study, Alleles, Prasugrel Hydrochloride, Maintenance dose, business.industry, Microfilament Proteins, Genetic Variation, Odds ratio, Middle Aged, Phosphoproteins, Clopidogrel, Cytochrome P-450 CYP2C19, Treatment Outcome, Purinergic P2Y Receptor Antagonists, Cardiology, Female, Aryl Hydrocarbon Hydroxylases, Cardiology and Cardiovascular Medicine, business, Cell Adhesion Molecules, medicine.drug
Abstract

The present study was performed to compare the influence of cytochrome P459 2C19 (CYP2C19) *2 and *17 genetic variants on the platelet response to clopidogrel and prasugrel maintenance therapy and to assess the relation between platelet reactivity and bleeding complications. A total of 730 patients were included (517 patients treated with clopidogrel 150 mg/day and 213 discharged with prasugrel 10 mg). Platelet reactivity was assessed at 1 month with the platelet reactivity index vasodilator-stimulated phosphoprotein (PRI VASP). High on-treatment platelet reactivity was defined as PRI VASP >50% and low on-treatment platelet reactivity (LTPR) as PRI VASP

Published
2013

20. Successful use of eltrombopag for surgical preparation in a patient with ANKRD26-related thrombocytopenia

Author

Jean-François Viallard, Noémie Saut, Mathieu Fiore, Marie-Christine Alessi, Centre de référence de pathologie plaquettaires, laboratoire d'hématologie, CHU Bordeaux [Bordeaux], 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), Service de Medecine Interne & Maladies Infectueuses, Hôpital Haut-Lévêque, CHU Bordeaux [Bordeaux]-Université Sciences et Technologies - Bordeaux 1, Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Sciences et Technologies - Bordeaux 1-CHU Bordeaux [Bordeaux]

Subjects
medicine.medical_specialty, Decreased platelet count, Eltrombopag, 030204 cardiovascular system & hematology, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, bleeding risk, Internal medicine, hemic and lymphatic diseases, Medicine, Platelet, Surgical preparation, ComputingMilieux_MISCELLANEOUS, transfusion, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, General Medicine, 3. Good health, ANKRD26-related thrombocytopenia, thrombocyte, Platelet transfusion, Increased risk, chemistry, intervention chirurgicale, platelet transfusion, business, eltrombopag, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract

Inherited thrombocytopenias are a heterogenous group of rare diseases characterized by decreased platelet count and increased risk of bleeding that ranges from life-threatening to very mild [1]. Pl...

Published
2016

21. Genome wide association study for plasma levels of natural anticoagulant inhibitors and protein C anticoagulant pathway: the MARTHA project

Author

Noémie Saut, Mark Lathrop, Choumous Kallel, William Cohen, David-Alexandre Trégouët, Tiphaine Oudot-Mellakh, Pierre-Emmanuel Morange, Marine Germain, and Diana Zelenika

Subjects
Genetics, medicine.medical_specialty, Antithrombin, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Hematology, Biology, Protein S, Endocrinology, Internal medicine, Genetic variation, medicine, biology.protein, SNP, Protein C, medicine.drug
Abstract

Summary Deficiencies of antithrombin (AT), protein C (PC) and protein S (PS) or an impaired PC anticoagulant pathway increase the risk of venous thrombosis (VT). By conducting a genome-wide association study (GWAS) on two independent samples of VT patients totalling 951 subjects typed for 472 173 single nucleotide polymorphisms (SNPs), we observed that common SNPs explain 21% and 27% of the genetic variance of plasma AT and PS levels, even though no SNP reached genome-wide significance. For PC, we showed that two PROCR SNPs, rs867186 (Ser219Gly) and rs6060278, additionally explained c. 20% (P =1 AE19 · 10 )31 ) of the variance of plasma PC levels. We also observed that c. 40% of the remaining genetic variance of PC levels could be due to yet unidentified common SNPs. The PROCR locus was also found to explain c. 8% (P

Published
2012

22. Clopidogrel Loading Dose Adjustment According to Platelet Reactivity Monitoring in Patients Carrying the 2C19*2Loss of Function Polymorphism

Author

Marie-Paule Giacomoni, Marie-Noelle Bartholomei, Laurence Camoin-Jau, Omar Ait Mokhtar, Sébastien Armero, Caroline Bonello-Burignat, Laurent Bonello, P. Aldebert, Françoise Dignat-George, Nathalie Bonello, Stephane Arques, Julien Mancini, Paul Barragan, Noémie Saut, and Franck Paganelli

Subjects
Male, Ticlopidine, Genotype, medicine.medical_treatment, cytochrome 2C19 polymorphism, Pharmacology, Loading dose, Polymerase Chain Reaction, Electrocardiography, P2Y12adenosine diphosphate receptor blocker, medicine, Humans, Platelet, cardiovascular diseases, Prospective Studies, vasodilator-stimulated phosphoprotein, Acute Coronary Syndrome, Angioplasty, Balloon, Coronary, Alleles, Monitoring, Physiologic, stent thrombosis, Polymorphism, Genetic, Dose-Response Relationship, Drug, business.industry, percutaneous coronary intervention, Microfilament Proteins, Vasodilator-stimulated phosphoprotein, Percutaneous coronary intervention, Blood Proteins, DNA, Middle Aged, Clopidogrel, Phosphoproteins, Platelet Activation, Blood proteins, Cytochrome P-450 CYP2C19, Dose–response relationship, Treatment Outcome, Anesthesia, Purinergic P2Y Receptor Antagonists, Female, Aryl Hydrocarbon Hydroxylases, business, Cardiology and Cardiovascular Medicine, Cell Adhesion Molecules, Pharmacogenetics, medicine.drug, Follow-Up Studies
Abstract

ObjectivesWe aimed to investigate the biological impact of a tailored clopidogrel loading dose (LD) according to platelet reactivity monitoring in carriers of the cytochrome (CYP) 2C19*2loss-of-function polymorphism undergoing percutaneous coronary intervention for an acute coronary syndromes.BackgroundCYP2C19*2polymorphism is associated with reduced clopidogrel metabolism and a worse prognosis after percutaneous coronary intervention.MethodA prospective multicenter study enrolling 411 patients with non–ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention was performed. Platelet reactivity was measured using the vasodilator-stimulated phosphoprotein (VASP) index, and a cutoff value of ≥50% was used to define high on-treatment platelet reactivity (HTPR). The genetic polymorphism of CYP2C19was determined by allele-specific polymerase chain reaction. In patients carrying CYP2C19*2and exhibiting HTPR after a first 600-mg LD of clopidogrel, dose adjustment was performed by using up to 3 additional 600 mg LDs to obtain a VASP index

Published
2010
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23. Common susceptibility alleles are unlikely to contribute as strongly as the FV and ABO loci to VTE risk: results from a GWAS approach

Author

Christine Biron-Andreani, Mark Lathrop, Gilles Pernod, Laurence Tiret, Marie-Christine Alessi, Pierre-Emmanuel Morange, Irène Juhan-Vague, Simon Heath, Noémie Saut, Jean-François Schved, Joseph Emmerich, Ludovic Drouet, David-Alexandre Trégouët, Diana Zelenika, and Pilar Galan

Subjects
Risk, Immunology, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Platelet Membrane Glycoproteins, Biology, Lower risk, Polymorphism, Single Nucleotide, Biochemistry, ABO Blood-Group System, Cytochrome P-450 Enzyme System, ABO blood group system, Genotype, Humans, Genetic Predisposition to Disease, Cytochrome P450 Family 4, cardiovascular diseases, Allele, Alleles, Genetics, Case-control study, Factor V, Venous Thromboembolism, Cell Biology, Hematology, equipment and supplies, Case-Control Studies, Genome-Wide Association Study
Abstract

Venous thromboembolism (VTE) is a complex disease that has a major genetic component of risk. To identify genetic factors that may modify the risk of VTE, we conducted a genome-wide association study by analyzing approximately 317 000 single nucleotide polymorphisms (SNPs) in 453 VTE cases and 1327 controls. Only 3 SNPs located in the FV and ABO blood group genes were found associated with VTE at a genome-wide significant level of 1.7 × 10−7. Detailed analysis of these SNPs in additional cohorts of more than 1700 cases and 1400 controls revealed that the association observed at the FV locus was the result of the increased risk mediated by the FV Leiden mutation, whereas O and A2 blood groups were found to be at lower risk for VTE. Apart from the FV and ABO loci, no other locus was found strongly associated with VTE. However, using this large cohort of subjects, we were able to replicate the mild effects of 2 nonsynonymous SNPs, rs1613662 in GP6 and rs13146272 in CYP4V2, recently suspected to be associated with VTE.

Published
2009

24. Polymorphisms of the tumor necrosis factor-alpha (TNF) and the TNF-alpha converting enzyme (TACE/ADAM17) genes in relation to cardiovascular mortality: the AtheroGene study

Author

Stefan Blankenberg, Noémie Saut, Christoph Bickel, Hans-Jürgen Rupprecht, David-Alexandre Trégouët, Tiphaine Godefroy, K.J. Lackner, Sandrine Barbaux, Irène Juhan-Vague, Franck Peiretti, Pierre Morange, Gilles Nalbone, Odette Poirier, and Laurence Tiret

Subjects
Male, medicine.medical_specialty, Genotype, medicine.medical_treatment, Single-nucleotide polymorphism, Inflammation, Coronary Artery Disease, ADAM17 Protein, Biology, Polymorphism, Single Nucleotide, Coronary artery disease, Gene Frequency, Internal medicine, Drug Discovery, medicine, Humans, Receptors, Tumor Necrosis Factor, Type II, Genetic Predisposition to Disease, Prospective cohort study, Alleles, Genetics (clinical), Aged, Tumor Necrosis Factor-alpha, Odds ratio, Middle Aged, medicine.disease, Molecular medicine, Survival Rate, ADAM Proteins, Phenotype, Endocrinology, Cytokine, Haplotypes, Receptors, Tumor Necrosis Factor, Type I, Molecular Medicine, Female, Tumor necrosis factor alpha, medicine.symptom
Abstract

Tumor necrosis factor (TNF) is a major cytokine involved in inflammatory reaction and a mortality predictor in patients with coronary artery disease (CAD). Plasma levels of soluble TNF (sTNF) depend on the rate of its synthesis but also on its shedding from cell surface, a mechanism mainly regulated by the TNF alpha converting enzyme (TACE or ADAM17). We investigated the relationship between ADAM17 and TNF polymorphisms, circulating levels of shed ADAM17 substrates (sTNF, sTNFR1 and sTNFR2), and cardiovascular risk in a prospective cohort of CAD patients. Five tag single-nucleotide polymorphisms (SNPs) of the ADAM17 gene as well as four previously described TNF SNPs were genotyped in the Atherogene Study composed of 1,400 CAD patients among which 136 died from a cardiovascular (CV) cause. sTNF, sTNFR1, and sTNFR2 concentrations were all significantly elevated in patients with future CV death, independently of other clinical/biological variables. While none of the studied TNF SNPs was associated with sTNF, sTNFR1, nor sTNFR2 levels, the ADAM17 -154A allele was found associated with a 14% increase of sTNF levels as compared to the -154C allele (p = 0.0066). Moreover, individuals carrying the 747Leu allele displayed a borderline increased risk of future cardiovascular death [odds ratio, 2.06 (1.05-4.04), p = 0.03]. These results suggest a role of ADAM17 in the regulation of sTNF plasma levels and identifies ADAM17 gene as a candidate for CAD. Tumor necrosis factor (TNF) is a major cytokine involved in inflammatory reaction and a mortality predictor in patients with coronary artery disease (CAD). We have studied the association of ADAM17 and TNF polymorphisms with circulating levels of shed ADAM17 substrates (sTNF, sTNFR1 and sTNFR2) and with cardiovascular risk in a large population of individuals with CAD (Atherogene Study, n = 1,400). Two newly identified polymorphisms, obtained by a systematic sequencing of the ADAM17 gene, C-154A and Ser747leu, slightly influence respectively sTNF plasma levels and the risk of cardiovascular death.

Published
2008

26. Lack of association between the 807 C/T polymorphism of glycoprotein Ia gene and post-treatment platelet reactivity after aspirin and clopidogrel in patients with acute coronary syndrome

Author

Jean-Louis Bonnet, Noémie Saut, Marc Lambert, Pierre-Emmanuel Morange, Thomas Cuisset, Irène Juhan-Vague, Marie Romero-Barra, Marie-Christine Alessi, Corinne Frere, Jacques Quilici, and Laurence Camoin

Subjects
Blood Platelets, Male, medicine.medical_specialty, Acute coronary syndrome, Ticlopidine, Genotype, Platelet Function Tests, Integrin alpha2, Myocardial Ischemia, Polymorphism, Single Nucleotide, Cytosine, Internal medicine, medicine, Humans, Platelet, Prospective Studies, Myocardial infarction, Phosphorylation, Aged, Aspirin, business.industry, Microfilament Proteins, Syndrome, Hematology, Middle Aged, Phosphoproteins, Platelet Activation, medicine.disease, Clopidogrel, Genotype frequency, Adenosine Diphosphate, P-Selectin, Treatment Outcome, Endocrinology, Acute Disease, Population study, Female, France, business, Cell Adhesion Molecules, Platelet Aggregation Inhibitors, Thymine, medicine.drug
Abstract

SummaryVariability in platelet response to antiplatelet therapy and its clinical relevance have been well described. However, the underlying mechanisms remain unclear. It was the aim of the present study to assess whether the response to aspirin and clopidogrel may be influenced by the 807 C/T polymorphism of the glycoprotein Ia (GpIa) gene in patients with non-ST elevation acute coronary syndrome (NSTE ACS). Six hundred one NSTE ACS patients were included in our study and were divided into three groups: CC homozygotes, CT heterozygotes ad TT homozygotes. All patients received loading doses of 600 mg clopidogrel and 250 mg aspirin at least 12 hours before blood samples were drawn. Post-treatment platelet reactivity was assessed by post treatment ADP 10 µM-induced platelet aggregation (ADP-Ag), VASP phosphorylation (PRI VASP) and P-selectin expression. Non-response to dual antiplatelet therapy was defined by high post-treatment platelet reactivity (HPPR= ADP-Ag>70%). Significant variability in the distribution of platelet parameters was observed in the overall study population. No significant difference in platelet parameters profiles was observed within patients having the same genotype, for ADP-Ag (p=0.33), PRIVASP (p=0.72) and P-selectin expression (p=0.37). The genotype frequencies of the 807 C/T polymorphism of the GpIa gene were similar in responders and non-responders defined by persistent HPPR (p=0.104). In conclusion, our study did not show any influence of 807 C/T polymorphism of GpIa gene on post-treatment platelet reactivity assessed by ADP-Ag, PRI VASP or P-selectin expression in 601 NSTE ACS patients.

Published
2007

27. Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism

Author

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)

Subjects
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.

Published
2015

28. Quantification of thrombin activatable fibrinolysis inhibitor (TAFI) gene polymorphism effects on plasma levels of TAFI measured with assays insensitive to isoform-dependent artefact

Author

Pierre-Emmanuel Morange, Jérôme Beltran, Mariana Grosley, Marie-Christine Alessi, Irène Juhan-Vague, Noémie Saut, David-Alexandre Trégouët, and Corinne Frere

Subjects
Male, Gene isoform, Carboxypeptidase B2, Genotype, medicine.medical_treatment, Myocardial Infarction, Enzyme-Linked Immunosorbent Assay, Biology, Sensitivity and Specificity, Gene Frequency, Risk Factors, Fibrinolysis, medicine, Humans, Protein Isoforms, Genetic Predisposition to Disease, Allele, Allele frequency, Gene, Alleles, Polymorphism, Genetic, Haplotype, Reproducibility of Results, Hematology, Molecular biology, Genetic Techniques, Haplotypes, Case-Control Studies, Gene polymorphism, Artifacts
Abstract

SummaryReports have reappraised the genotype-dependent variation of Thrombin Activatable Fibrinolysis Inhibitor (TAFI), demonstrating that, in some enzyme-linked immunosorbent assays (ELISA), decreased antibody reactivity towards the TAFI 325 Ile isoform led to erroneous TAFI levels. Assays free of this artefact are required to evaluate the contribution of theTAFI gene polymorphisms toTAFI level variability.TAFI levels were measured in 209 individuals with both immunological and functional assays. Each assay was characterized, in particular for its reactivity towards the 325 Thr and Ile isoforms. Two ELISAs were found to have a lower reactivity towards the Ile isoform, leading to an overesti-mate of the magnitude of variation between two different genotypes. In contrast, one ELISA, as well as functional assays, was found to be free of genotype-dependent artefact constituting a reliable method to detect true quantitative variations of TAFI levels. Using these reliable methods, univariate and haplotype analyses revealed that TAFI gene polymorphisms explain 25% of TAFI level variability. This effect seems to be the consequence of the joint independent action of two polymorphisms, one in the 5’ (G-1102T) and the other in the 3’ region (T+1583A) of the TAFI gene.

Published
2005

29. Biological and genetic factors influencing plasma factor VIII levels in a healthy family population: results from the Stanislas cohort

Author

Pierre Morange, L. Pellegrina, Marie-Christine Alessi, Corinne Frere, Sophie Visvikis, Noémie Saut, Laurence Tiret, Irène Juhan-Vague, and David-Alexandre Trégouët

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Genotype, animal diseases, Population, Biology, ABO Blood-Group System, Cohort Studies, Von Willebrand factor, Polymorphism (computer science), hemic and lymphatic diseases, ABO blood group system, Internal medicine, Blood plasma, medicine, Humans, Genetic variability, Allele, education, Blood Coagulation, Receptors, Lipoprotein, education.field_of_study, Binding Sites, Factor VIII, Polymorphism, Genetic, Lipoprotein receptor-related protein, Hematology, Pedigree, Endocrinology, Immunology, biology.protein
Abstract

The mechanisms underlying the variability of factor VIII (FVIII) levels are still poorly understood. The only receptor of FVIII identified so far is the lipoprotein receptor-related protein (LRP), which is thought to be involved in FVIII degradation. We aimed to characterize biological and genetic factors related to FVIII variability, focusing on coding polymorphisms of the LRP gene and polymorphisms potentially detected by molecular screening of the LRP-binding domains of the FVIII gene. Plasma FVIII coagulant activity (FVIII:C) and von Willebrand factor (VWF:Ag) antigen levels were measured in a sample of 100 healthy nuclear families (200 parents and 224 offspring). The ABO blood group and the three coding polymorphisms of the LRP gene (A217V, D2080N and C766T) were genotyped. Lipids and anthropometric factors poorly contributed to the variability of FVIII:C (

Published
2005

30. KNG1 Ile581Thr and susceptibility to venous thrombosis

Author

Jean-Charles Lambert, Philippe Amouyel, William Cohen, Marion Bertrand, Marie-Christine Alessi, David-Alexandre Trégouët, Pierre-Emmanuel Morange, Guillemette Antoni, Joseph Emmerich, Tiphaine Oudot-Mellakh, Lorna M. Lopez, Anne-Marie Dupuy, Mark Lathrop, Marine Germain, Luc Letenneur, and Noémie Saut

Subjects
Male, Threonine, medicine.medical_specialty, Immunology, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, Biochemistry, Gastroenterology, Gene Frequency, Internal medicine, Humans, Medicine, Genetic Predisposition to Disease, Isoleucine, Allele frequency, Alleles, Venous Thrombosis, medicine.diagnostic_test, Kininogens, business.industry, Case-control study, Cell Biology, Hematology, Odds ratio, medicine.disease, Confidence interval, Venous thrombosis, Amino Acid Substitution, Case-Control Studies, Anesthesia, Female, business, Genome-Wide Association Study, circulatory and respiratory physiology, Partial thromboplastin time
Abstract

Three single nucleotide polymorphisms (SNPs) were recently found to be associated with activated partial thromboplastin time (aPTT). Because shortened aPTT levels have been observed in patients experiencing venous thrombosis (VT), we investigated the effects of these 3 aPTT-associated SNPs, rs2731672, rs9898, and rs710446, on the risk of VT in a sample of 1110 healthy patients and 1542 patients with VT. Among the 3 tested SNPs, only rs710446 was associated with VT risk; the rs710446-C allele was associated with an increased risk of VT (odds ratio 1.196, 95% confidence interval 1.071-1.336, P = .0012). This association also was observed in an independent sample of 590 controls and 596 patients (odds ratio 1.171, 95% confidence interval 0.889-1.541, P = .059). We also confirmed that the rs710446-C allele was associated with decreased aPTT levels, making this nonsynonymous Ile581Thr variant a new genetic risk factor for VT.

Published
2011

31. Multilocus Genetic Risk Scores for Venous Thromboembolism Risk Assessment

Author

Juan Souto, Joan Vila, José Manuel Soria, Eduardo Salas, Roberto Elosua, Manel Moyano, David-Alexandre Trégouët, Noémie Saut, José Mateo, Pierre-Emmanuel Morange, Hospital de la Santa Creu i Sant Pau, 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), IMIM-Hospital del Mar, Generalitat de Catalunya, CIBER de Epidemiología y Salud Pública (CIBERESP), Gendiag Barcelona, 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 (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-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], and HAL UPMC, Gestionnaire

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Genotype, Risk Assessment, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Predictive Value of Tests, Internal medicine, medicine, Factor V Leiden, Genetics, Odds Ratio, risk factors, Humans, Genetic Predisposition to Disease, Genetic Testing, thrombosis, Original Research, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Receiver operating characteristic, business.industry, Incidence, Area under the curve, Factor V, Genetic Variation, veins, Venous Thromboembolism, Middle Aged, Explained variation, medicine.disease, Thrombosis, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Genetic marker, Spain, Case-Control Studies, Mutation, [SDV.GEN.GPO] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], tests, Regression Analysis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, Prothrombin, Cardiology and Cardiovascular Medicine, Risk assessment, business, Venous thromboembolism, Multilocus Sequence Typing
Abstract

Background Genetics plays an important role in venous thromboembolism ( VTE ). Factor V Leiden ( FVL or rs6025) and prothrombin gene G20210A ( PT or rs1799963) are the genetic variants currently tested for VTE risk assessment. We hypothesized that primary VTE risk assessment can be improved by using genetic risk scores with more genetic markers than just FVL ‐rs6025 and prothrombin gene PT ‐rs1799963. To this end, we have designed a new genetic risk score called Thrombo inCode (TiC). Methods and Results TiC was evaluated in terms of discrimination (Δ of the area under the receiver operating characteristic curve) and reclassification ( integrated discrimination improvement and net reclassification improvement ). This evaluation was performed using 2 age‐ and sex‐matched case–control populations: SANTPAU (248 cases, 249 controls) and the Marseille Thrombosis Association study ( MARTHA ; 477 cases, 477 controls). TiC was compared with other literature‐based genetic risk score s. TiC including F5 rs6025/rs118203906/rs118203905, F2 rs1799963, F12 rs1801020, F13 rs5985, SERPINC 1 rs121909548, and SERPINA 10 rs2232698 plus the A1 blood group (rs8176719, rs7853989, rs8176743, rs8176750) improved the area under the curve compared with a model based only on F5‐ rs6025 and F2‐ rs1799963 in SANTPAU (0.677 versus 0.575, P MARTHA (0.605 versus 0.576, P =0.008). TiC showed good integrated discrimination improvement of 5.49 ( P SANTPAU and 0.96 ( P =0.045) for MARTHA . Among the genetic risk score s evaluated, the proportion of VTE risk variance explained by TiC was the highest. Conclusions We conclude that TiC greatly improves prediction of VTE risk compared with other genetic risk score s. TiC should improve prevention, diagnosis, and treatment of VTE .

Published
2014

32. A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential

Author

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

Subjects
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

33. The human Y chromosome genes BPY2, CDY1 and DAZ are not essential for sustained fertility

Author

Noémie Saut, Nicolas Lévy, Michael J. Mitchell, P. Terriou, and A. Navarro

Subjects
Adult, Male, Infertility, Embryology, DNA, Complementary, Molecular Sequence Data, BPY2, Biology, Y chromosome, Y Chromosome, Genetics, medicine, Humans, Gene family, Allele, Molecular Biology, Gene, Southern blot, Azoospermia, Base Sequence, Nuclear Proteins, Proteins, RNA-Binding Proteins, Obstetrics and Gynecology, Deleted in Azoospermia 1 Protein, Oligospermia, Cell Biology, medicine.disease, Pedigree, Reproductive Medicine, Female, Chromosome Deletion, Developmental Biology
Abstract

Deletions of the AZFc interval of the human Y chromosome are found in >5% of male patients with idiopathic infertility and are associated with a severely reduced sperm count. The most common deletion type is large (>1 Mb) and removes members of the Y-borne testis-specific gene families of BPY2, CDY1, DAZ, PRY, RBMY2 and TTY2, which are candidate AZF genes. Four exceptional individuals who have transmitted a large AZFc deletion naturally to their infertile sons have, however, been described. In three cases, transmission was to an only son, but in the fourth case a Y chromosome, shown to be deleted for all copies of DAZ, was transmitted from a father to his four infertile sons. Here we present a second family of this latter type and demonstrate that an AZFc-deleted Y chromosome lacking not only DAZ, but also BPY2 and CDY1, has been transmitted from a father to his three infertile sons. Polymerase chain reaction (PCR) and Southern blot analyses revealed no difference in the size of the AZFc deletion in the father and his sons. We propose that the father carries rare alleles of autosomal or X-linked loci which suppress the infertility that is frequently associated with the absence of AZFc.

Published
2000

34. Dendritic Cells Permit Identification of Genes Encoding MHC Class II–Restricted Epitopes of Transplantation Antigens

Author

Stipo Jurcevic, Michael J. Mitchell, P. Ellis, Elizabeth Simpson, Eddie A. James, Diane Scott, Caroline Addey, and Noémie Saut

Subjects
Eukaryotic Initiation Factor-2, Genes, MHC Class II, H-Y Antigen, Molecular Sequence Data, Immunology, Epitopes, T-Lymphocyte, Mice, Transgenic, Major histocompatibility complex, Epitope, DEAD-box RNA Helicases, Minor Histocompatibility Antigens, Mice, Antigen, Histocompatibility Antigens, Animals, Immunology and Allergy, Amino Acid Sequence, Histone Demethylases, MHC class II, COS cells, biology, H-2 Antigens, Nuclear Proteins, Proteins, Dendritic Cells, MHC restriction, Virology, Molecular biology, Immunity, Innate, Histocompatibility, Mice, Inbred C57BL, Infectious Diseases, Gene Expression Regulation, Mice, Inbred CBA, biology.protein, Female, Peptides, CD8
Abstract

Minor or histocompatibility (H) antigens are recognized by CD4 + and CD8 + T lymphocytes as short polymorphic peptides associated with MHC molecules. They are the targets of graft versus host and graft versus leukemia responses following bone marrow transplantation between HLA-identical siblings. Several genes encoding class I–restricted minor H epitopes have been identified, but approaches used for these have proved difficult to adapt for cloning class II–restricted minor H genes. We have combined the unique antigen-presenting properties of dendritic cells and high levels of episomal expression following transfection of COS cells to identify a Y chromosome gene encoding two HY peptide epitopes, HYA b and HYE k .

Published
2000

35. ABO blood group and von Willebrand factor levels partially explained the incomplete penetrance of congenital thrombophilia

Author

Marie-Christine Alessi, Noémie Saut, David-Alexandre Trégouët, William Cohen, Géraldine Lavigne, Sophie Bouvet, Christel Castelli, Pierre-Emmanuel Morange, Dominique Brunet, Marie-Françoise Aillaud, and M. C. Barthet

Subjects
Adult, Male, Risk, medicine.medical_specialty, Thrombophilia, Gastroenterology, ABO Blood-Group System, Von Willebrand factor, Internal medicine, ABO blood group system, von Willebrand Factor, medicine, Coagulopathy, Factor V Leiden, Humans, Aged, Venous Thrombosis, Factor VIII, biology, business.industry, Antithrombin, Middle Aged, medicine.disease, Venous thrombosis, Immunology, biology.protein, Female, Cardiology and Cardiovascular Medicine, business, Protein C, medicine.drug
Abstract

Objective— We aimed to study the association among ABO blood group, von Willebrand factor, factor VIII plasma levels, and the risk of venous thrombosis (VT) in a cohort of 1774 relatives from 500 families with inherited thrombophilia. Methods and Results— One hundred sixty-one of the 1774 relatives had a VT. Different risk groups were formed: no, low-(factor V Leiden or F2G20210A heterozygous carriers), and high-risk thrombophilia (antithrombin, protein C, protein S, factor V Leiden, or F2G20210A homozygous carriers and combined defects). Compared with group O, AB blood group was associated with increased risk of VT: hazard ratio (HR)=3.8 (2.0–7.2). The effect of blood group A and B was milder (HR=1.6 [1.1–2.5] and 1.8 [1.0–3.3], respectively). An increased risk of VT was observed with increasing levels of von Willebrand factor and factor VIII plasma levels (HR=2.96 [1.92–4.56] and HR=2.60 [1.92–4.56] for third versus first tertile of von Willebrand factor and factor VIII plasma levels, respectively). In multivariate analysis, AB group (HR=2.3 [1.1–4.8]), high-risk thrombophilia (HR=2.8 [1.6–4.6]), and high von Willebrand factor levels (HR=2.3 [1.3–4.0]) were significantly associated with increased risk of VT. The risk of VT in individuals with high-risk thrombophilia and AB group was 14.4× higher than in those without thrombophilia and O group (5.0–41.4). Conclusion— ABO blood group modifies the risk of VT in families with hereditary thrombophilia. Phenotyping of the ABO blood group should be performed to better assess the risk of VT in asymptomatic individuals from thrombophilic families.

Published
2012

36. Genome wide association study for plasma levels of natural anticoagulant inhibitors and protein C anticoagulant pathway: the MARTHA project

Author

Tiphaine, Oudot-Mellakh, William, Cohen, Marine, Germain, Noémie, Saut, Choumous, Kallel, Diana, Zelenika, Mark, Lathrop, David-Alexandre, Trégouët, and Pierre-Emmanuel, Morange

Subjects
Adult, Male, Venous Thrombosis, Endothelial Protein C Receptor, Receptors, Cell Surface, Middle Aged, Polymorphism, Single Nucleotide, Protein S, Antigens, CD, Genetic Loci, Risk Factors, Crotalid Venoms, Humans, Female, Antithrombin Proteins, Blood Coagulation, Genome-Wide Association Study, Protein C, Retrospective Studies
Abstract

Deficiencies of antithrombin (AT), protein C (PC) and protein S (PS) or an impaired PC anticoagulant pathway increase the risk of venous thrombosis (VT). By conducting a genome-wide association study (GWAS) on two independent samples of VT patients totalling 951 subjects typed for 472 173 single nucleotide polymorphisms (SNPs), we observed that common SNPs explain 21% and 27% of the genetic variance of plasma AT and PS levels, even though no SNP reached genome-wide significance. For PC, we showed that two PROCR SNPs, rs867186 (Ser219Gly) and rs6060278, additionally explained c. 20% (P = 1·19 × 10(-31)) of the variance of plasma PC levels. We also observed that c. 40% of the remaining genetic variance of PC levels could be due to yet unidentified common SNPs. The PROCR locus was also found to explain c. 8% (P10(-10)) of agkistrodon contortrix venom (ACV) (exploring the PC pathway) variability which was under the main control of the F5 and F2 loci that further explained about 40% and 10%, respectively. We presented here the first GWAS for plasma AT and free-PS levels and ACV in Caucasian samples. We identified three independent loci associated with ACV (F2, F5 and PROCR) and replicated two independent effects on plasma PC levels at the PROCR locus.

Published
2012

37. CYP2C19*2 and *17 Alleles Have a Significant Impact on Platelet Response and Bleeding Risk in Patients Treated With Prasugrel After Acute Coronary Syndrome

Author

Thomas Cuisset, L. Fourcade, Jean-Louis Bonnet, Marie Loosveld, Shirley Beguin, Charlotte Grosdidier, Marie-Christine Alessi, Christel Castelli, Jacques Quilici, Bénédicte Gaborit, Pierre Julien Moro, Noémie Saut, Pierre-Emmanuel Morange, Cuisset, Thomas, Service de Cardiologie, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), 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), Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Biostatistique, Epidémiologie, Santé Publique et Informatique Médicale (BESPIM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Equipe Mobile d'Aide à l'Investigation (EMAI), Assistance Publique - Hôpitaux de Marseille (APHM)-CHU Marseille, Service de Pathologie Cardiovasculaire, Hôpital HIA Laveran, and Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes)

Subjects
Blood Platelets, Male, medicine.medical_specialty, Acute coronary syndrome, Prasugrel, Hemorrhage, Thiophenes, CYP2C19, 030204 cardiovascular system & hematology, Gastroenterology, Piperazines, acute coronary syndrome, 03 medical and health sciences, Postoperative Complications, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Risk Factors, Internal medicine, medicine, Humans, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, Alleles, Prasugrel Hydrochloride, business.industry, Odds ratio, Middle Aged, bleeding, Clopidogrel, medicine.disease, prasugrel, 3. Good health, Surgery, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cytochrome P-450 CYP2C19, genotyping, platelet testing, Female, Aryl Hydrocarbon Hydroxylases, business, Cardiology and Cardiovascular Medicine, TIMI, medicine.drug
Abstract

International audience; OBJECTIVES: The present study was designed to assess the effect of genetic variants on chronic biological response to prasugrel and bleeding complications. BACKGROUND: CYP2C19*2 loss-of-function allele and CYP2C19*17 gain-of-function allele have been linked with response to clopidogrel, but preliminary data did not show any significant influence of these alleles on prasugrel effect. METHODS: A total of 213 patients undergoing successful coronary stenting for acute coronary syndrome and discharged with prasugrel 10 mg daily were included. Prasugrel response was assessed at 1 month with the platelet reactivity index (PRI) vasodilator-stimulated phosphoprotein (VASP) and high on-treatment platelet reactivity (HTPR) defined as PRI VASP > 50% and hyper-response as PRI VASP

Published
2012

38. Association of soluble endothelial protein C receptor plasma levels and PROCR rs867186 with cardiovascular risk factors and cardiovascular events in coronary artery disease patients: The AtheroGene Study

Author

Thomas Münzel, Choumous Kallel, Stefan Blankenberg, Noémie Saut, David-Alexandre Trégouët, Renate B. Schnabel, William Cohen, Pierre-Emmanuel Morange, Hans J. Rupprecht, Christoph Bickel, BMC, Ed., 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), Department of General and Interventional Cardiology, University Heart Center Hamburg, Department of Medicine II, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Federal Armed Forces Central Hospital Koblenz, Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by a grant of the Programme National de Recherche sur les Maladies Cardiovasculaires 2006 (A06034AS), by the 'Stiftung Rheinland-Pfalz für Innovation', Ministry for Science and Education (AZ 15202-386261/545), Mainz, by the MAIFOR grant 2001 of the Johannes Gutenberg-University Mainz, Germany and by a grant from the Fondation de France (no. 2002004994)., Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Johannes Gutenberg - Universität Mainz (JGU)

Subjects
Male, lcsh:Internal medicine, medicine.medical_specialty, Acute coronary syndrome, lcsh:QH426-470, Cardiovascular risk factors, Receptors, Cell Surface, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030204 cardiovascular system & hematology, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Polymorphism, Single Nucleotide, Coronary artery disease, Endothelial protein C receptor, Angina Pectoris, 03 medical and health sciences, 0302 clinical medicine, Antigens, CD, Risk Factors, Internal medicine, Genetics, medicine, Humans, Genetics(clinical), Acute Coronary Syndrome, lcsh:RC31-1245, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, medicine.disease, lcsh:Genetics, Coagulation, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cardiovascular Diseases, Immunology, Cardiology, Biomarker (medicine), Female, Biomarkers, Protein C, Research Article, medicine.drug, Haemostasis
Abstract

Background Blood coagulation is an essential determinant of coronary artery disease (CAD). Soluble Endothelial Protein C Receptor (sEPCR) may be a biomarker of a hypercoagulable state. We prospectively investigated the relationship between plasma sEPCR levels and the risk of cardiovascular events (CVE). Methods We measured baseline sEPCR levels in 1673 individuals with CAD (521 with acute coronary syndrome [ACS] and 1152 with stable angina pectoris [SAP]) from the AtheroGene cohort. During a median follow up of 3.7 years, 136 individuals had a CVE. In addition, 891 of these CAD patients were genotyped for the PROCR rs867186 (Ser219Gly) variant. Results At baseline, sEPCR levels were similar in individuals with ACS and SAP (median: 111 vs. 115 ng/mL respectively; p=0.20). Increased sEPCR levels were found to be associated with several cardiovascular risk factors including gender (p=0.006), soluble Tissue Factor levels (p=0.0001), diabetes (p=0.0005), and factors reflecting impaired renal function such as creatinine and cystatin C (p-200) but did not associate with CVE risk. Conclusion Our findings show that in patients with CAD, circulating sEPCR levels are related to classical cardiovascular risk factors and renal impairment but are not related to long-term incidence of CVE.

Published
2012

39. Usefulness of high clopidogrel maintenance dose according to CYP2C19 genotypes in clopidogrel low responders undergoing coronary stenting for non ST elevation acute coronary syndrome

Author

Thomas Cuisset, Noémie Saut, L. Fourcade, William Cohen, Mathieu Pankert, Bénédicte Gaborit, Jacques Quilici, Marie-Christine Alessi, Pierre-Emmanuel Morange, Patrizia Carrieri, and Jean Louis Bonnet

Subjects
Male, medicine.medical_specialty, Acute coronary syndrome, Ticlopidine, Genotype, Platelet Function Tests, Endpoint Determination, medicine.medical_treatment, Population, Drug Resistance, CYP2C19, Loading dose, Polymerase Chain Reaction, Risk Assessment, Statistics, Nonparametric, Risk Factors, Internal medicine, medicine, Humans, cardiovascular diseases, Prospective Studies, Acute Coronary Syndrome, education, Alleles, education.field_of_study, Analysis of Variance, Chi-Square Distribution, Maintenance dose, business.industry, ST elevation, Percutaneous coronary intervention, Middle Aged, medicine.disease, Clopidogrel, Flow Cytometry, Cytochrome P-450 CYP2C19, Treatment Outcome, Cardiology, Female, Stents, Aryl Hydrocarbon Hydroxylases, Cardiology and Cardiovascular Medicine, business, Platelet Aggregation Inhibitors, circulatory and respiratory physiology, medicine.drug
Abstract

The cytochrome P450 (CYP) 2C19*2 loss-of-function allele has been associated with impaired clopidogrel response and worse prognosis in clopidogrel-treated patients. The benefit of tailored therapy according to platelet function test results remains unclear, and the potential effect of genotypes on this benefit has not been addressed in unstable patients. The present study was designed to evaluate the benefit of tailored therapy with a higher maintenance dose according to CYP2C19 genotypes in patients identified as nonresponders who underwent percutaneous coronary intervention for non-ST-segment elevation acute coronary syndromes. Three hundred forty-six consecutive patients were enrolled and received a loading dose of 600 mg, including 86 *2 carriers (13 homozygotes and 73 heterozygotes) and 260 *2 noncarriers. Clopidogrel response, assessed with platelet reactivity index vasoactive-stimulated phosphoprotein, was significantly affected by genotype, with lower clopidogrel response in CYP2C19*2 allele carriers (p = 0.01). Accordingly, the rate of clopidogrel nonresponse was higher in CYP2C19*2 allele carriers (53% vs 41%, p = 0.04). All clopidogrel nonresponders (n = 151), including 105 *2 noncarriers and 46 *2 carriers, received high 150-mg clopidogrel maintenance doses at discharge to overcome initial low response. After 1 month, high maintenance doses overcame clopidogrel low response in only 44% of the whole population and significantly less frequently in *2 carriers than in noncarriers (28% vs 50%, p = 0.01). In conclusion, higher clopidogrel maintenance doses were able to overcome clopidogrel low response in fewer than half of clopidogrel low responders who underwent percutaneous coronary intervention for non-ST-segment elevation acute coronary syndromes. The benefit of this tailored therapy was significantly reduced in CYP2C19*2 carriers. Therefore, these patients might require alternative strategies with new P2Y₁₂ blockers.

Published
2011

40. Association of vitronectin and plasminogen activator inhibitor-1 levels with the risk of metabolic syndrome and type 2 diabetes mellitus. Results from the D.E.S.I.R. prospective cohort

Author

Bénédicte Fontaine-Bisson, Pierre-Emmanuel Morange, Noémie Saut, Marie-Christine Alessi, Beverley Balkau, Viviane Nicaud, David-Alexandre Trégouët, Irène Juhan-Vague, Céline Lange, Frédéric Fumeron, Ilse Scroyen, Olivier Lantieri, and Michel Marre

Subjects
0301 basic medicine, Adult, Male, Risk, medicine.medical_specialty, Time Factors, Genotype, Type 2 diabetes, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Insulin resistance, Internal medicine, Plasminogen Activator Inhibitor 1, medicine, Humans, Vitronectin, Prospective cohort study, Aged, Metabolic Syndrome, biology, business.industry, Type 2 Diabetes Mellitus, Hematology, Middle Aged, medicine.disease, Prognosis, 030104 developmental biology, Endocrinology, chemistry, Diabetes Mellitus, Type 2, Plasminogen activator inhibitor-1, Case-Control Studies, biology.protein, Female, Metabolic syndrome, business, Plasminogen activator, Biomarkers
Abstract

SummaryIt was the objective of this study to investigate the relation between vitronectin and plasminogen activator inhibitor (PAI)-1 plasma levels with nine-year incidences of the metabolic syndrome (MetS) and of type 2 diabetes mellitus (T2DM). Baseline plasma concentrations of vitronectin and PAI-1 were measured in 627 healthy participants from the prospective D.E.S.I.R. cohort who subsequently developed MetS (n=487) and T2DM (n=182) over a nine-year follow-up (42 presented both) and who were matched with two healthy control subjects each by use of a nested case-control design. Parameters composing the MetS explained about 20% of plasma vitronectin levels. An increase of one standard deviation of vitronectin was associated with increased risks of both the MetS (odds ratio [OR] = 1.21 [1.07 – 1.37], p = 0.003) and T2DM (OR = 1.24 [1.01 – 1.53], p = 0.045). Corresponding ORs for PAI-1 levels were 1.46 [1.27 – 1.68] (p < 10−4) and 1.40 [1.14 – 1.72] (p = 0.0012). However, the effects of vitronectin and PAI-1 levels on outcomes were not independent. The vitronectin–MetS association was restricted to individuals with low to modest PAI-1 levels (OR = 1.33 [1.14 – 1.54], p = 0.0003) while no association was observed in individuals with high PAI-1 levels (OR = 0.87 [0.68 – 1.10], p = 0.24), the test for interaction being highly significant (p = 0.0009). In conclusion, baseline plasma vitronectin is a marker of incident MetS at nine years. Its predictive ability for MetS and T2DM should not be assessed independently of PAI-1 levels.

Published
2011

41. Impact on venous thrombosis risk of newly discovered gene variants associated with FVIII and VWF plasma levels

Author

Pierre Morange, Noémie Saut, David-Alexandre Trégouët, Joseph Emmerich, and Guillemette Antoni

Subjects
Male, Genome-wide association study, Bioinformatics, Polymorphism, Single Nucleotide, Risk Assessment, Gene Frequency, Polymorphism (computer science), Risk Factors, von Willebrand Factor, medicine, Odds Ratio, Humans, Genetic Predisposition to Disease, Allele frequency, Gene, Venous Thrombosis, Factor VIII, business.industry, Case-control study, Hematology, Odds ratio, medicine.disease, Venous thrombosis, Logistic Models, Phenotype, Case-Control Studies, Female, France, Risk assessment, business, Biomarkers, Genome-Wide Association Study
Published
2010

42. Complete deletion of the AZFb interval from the Y chromosome in an oligozoospermic man

Author

Marie-Roberte Guichaoua, Michael J. Mitchell, Rachel Levy, Guy Longepied, Catherine Metzler-Guillemain, Noémie Saut, I. Aknin-Seifer, and Anne-Marie Frances

Subjects
Adult, Male, Molecular Sequence Data, Locus (genetics), Biology, Y chromosome, Male infertility, Meiosis, Spermatocytes, medicine, Humans, Spermatogenesis, Aged, Azoospermia, Sequence Deletion, Genetics, Chromosomes, Human, Y, Base Sequence, Rehabilitation, Synapsis, Obstetrics and Gynecology, Oligospermia, medicine.disease, Synaptonemal complex, Chromosome Pairing, medicine.anatomical_structure, Reproductive Medicine, Germ cell
Abstract

background: Deletion of the entire AZFb interval from the Y chromosome is strictly associated with azoospermia arising from maturation arrest during meiosis. Here, we describe the exceptional case of an oligozoospermic man, 13-1217, with an AZFb + c (P5/distal-P1) deletion. Through the characterization of this patient, and two AZFb (P5/proximal-P1) patients with maturation arrest, we have explored three possible explanations for his exceptionally progressive spermatogenesis. methods and results: We have determined the precise breakpoints of the deletion in 13-1217, and shown that 13-1217 is deleted for more AZFb material than one of the AZFb-deleted men (13-5349). Immunocytochemical analysis of spermatocytes with an antibody against a synaptonemal complex component indicates synapsis to be largely unaffected in 13-1217, in contrast to 13-5349 where extended asynapsis is frequent. Using PCR-based analyses of RNA and DNA from the same testicular biopsy, we show that 13-1217 expresses post-meiotic germ cell markers in the absence of genomic DNA and transcripts from the AZFb and AZFc intervals. We have determined the Y chromosome haplogroup of 13-1217 to be HgL-M185. conclusions: Our results indicate that the post-meiotic spermatogenesis in 13-1217 is not a consequence of mosaicism or retention of a key AZFb gene. On the contrary, since the Hg-L Y chromosome carried by 13-1217 is uncommon in Western Europe, a Y-linked modifier locus remains a possible explanation for the oligozoospermia observed in patient 13-1217. Further cases must now be studied to understand how germ cells complete spermatogenesis in the absence of the AZFb interval.

Published
2010

43. A follow-up study of a genome-wide association scan identifies a susceptibility locus for venous thrombosis on chromosome 6p24.1

Author

Marie-Christine Alessi, Mark Lathrop, Simon Heath, Diana Zelenika, Jessy Brocheton, Jean-François Schved, Marine Germain, Pilar Galan, Ewa Ninio, Stefan Blankenberg, Thomas Münzel, Joseph Emmerich, Irene D. Bezemer, Christine Biron-Andreani, François Cambien, Aurélien Delluc, Noémie Saut, Tanja Zeller, David-Alexandre Trégouët, Ludovic Drouet, Frits R. Rosendaal, Laurence Tiret, Pierre-Emmanuel Morange, Viviane Nicaud, Hervé Durand, Stefan-Martin Brand-Herrmann, Gwenaelle Burgos, Lance A. Bare, Gilles Pernod, 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), Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Techniques pour l'Evaluation et la Modélisation des Actions de la Santé (TIMC-IMAG-ThEMAS), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Service de Biochimie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR6, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Department of Medicine II, Johannes Gutenberg - Universität Mainz (JGU), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Génomique d'Evry (IG), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Department of General and Interventional Cardiology, University Heart Center Hamburg, Risque Thrombotique et Mecanismes de l'Hemostase (U765), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Risque Thrombotique et Mécanismes de l'Hémostase (U765), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR14-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -CHU Saint-Eloi, ThEMAS, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Unité de Recherche en Epidémiologie Nutritionnelle ( UREN ), Université Paris 13 ( UP13 ) -Institut National de la Recherche Agronomique ( INRA ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière-IFR6, Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Département de Médecine Interne et Pneumologie [Brest] ( DMIP - Brest ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Groupe d'Etude de la Thrombose de Bretagne Occidentale ( GETBO ), Université de Brest ( UBO ), Johannes Gutenberg-University Mainz, Hôpital de la Timone [CHU - APHM] ( TIMONE ), Institut de Génomique d'Evry ( IG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Risque Thrombotique et Mecanismes de l'Hemostase ( U765 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-IFR6, Université de Brest (UBO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-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 Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)

Subjects
MESH : Transcription Factors, [SDV]Life Sciences [q-bio], Genome-wide association study, 030204 cardiovascular system & hematology, MESH : Chromosomes, Human, Pair 6, 0302 clinical medicine, Genetics(clinical), Genetics (clinical), Genetics, Venous Thrombosis, 0303 health sciences, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, MESH: Follow-Up Studies, MESH: Transcription Factors, MESH : Venous Thrombosis, MESH: Case-Control Studies, DNA-Binding Proteins, Chromosomes, Human, Pair 6, MESH : DNA-Binding Proteins, Erratum, MESH : Genome-Wide Association Study, MESH : Case-Control Studies, MESH: Chromosomes, Human, Pair 6, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Genetic determinism, 03 medical and health sciences, Report, Genetic predisposition, Humans, Genetic Predisposition to Disease, Allele, Gene, 030304 developmental biology, MESH: Humans, [ SDV ] Life Sciences [q-bio], MESH : Humans, linking inflammation protein atherothrombosis sequence risk, Case-control study, Chromosome, MESH : Follow-Up Studies, Case-Control Studies, MESH: Genome-Wide Association Study, MESH: Venous Thrombosis, MESH : Genetic Predisposition to Disease, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins, Follow-Up Studies, Genome-Wide Association Study, Transcription Factors
Abstract

International audience; To identify genetic susceptibility factors conferring increased risk of venous thrombosis (VT), we conducted a multistage study, following results of a previously published GWAS that failed to detect loci for developing VT. Using a collection of 5862 cases with VT and 7112 healthy controls, we identified the HIVEP1 locus on chromosome 6p24.1 as a susceptibility locus for VT. Indeed, the HIVEP1 rs169713C allele was associated with an increased risk for VT, with an odds ratio of 1.20 (95% confidence interval 1.13-1.27, p = 2.86 x 10(-9)). HIVEP1 codes for a protein that participates in the transcriptional regulation of inflammatory target genes by binding specific DNA sequences in their promoter and enhancer regions. The current results provide the identification of a locus involved in VT susceptibility that lies outside the traditional coagulation/fibrinolysis pathway.

Published
2010

44. Adrenergic receptor polymorphisms and platelet reactivity after treatment with dual antiplatelet therapy with aspirin and clopidogrel in acute coronary syndrome

Author

Michalis Hamilos, Corinne Frere, Emanuele Barbato, Noémie Saut, Mark Eijgelsheim, Jean Louis Bonnet, William Wijns, Leen Delrue, Thomas Cuisset, Jozef Bartunek, Katia M.C. Verhamme, Marie-Christine Alessi, Cuisset, T., Hamilos, M., Delrue, L., Frere, C., Verhamme, K., Bartunek, J., Saut, N., Bonnet, J. L., Eijgelsheim, M., Wijns, W., Alessi, M. C., and Barbato, Emanuele

Subjects
Male, Platelet Aggregation, arginine, acetylsalicylic acid, beta 2 adrenergic receptor, clopidogrel, vasodilator stimulated phosphoprotein, acute coronary syndrome, adult, aged, article, controlled study, DNA polymorphism, female, human, major clinical study, male, priority journal, protein phosphorylation, screening test, thrombocyte aggregation, treatment outcome, Acute Coronary Syndrome, Adenosine Diphosphate, Aged, Aspirin, Cell Adhesion Molecules, Chi-Square Distribution, Drug Therapy, Combination, Female, Gene Frequency, Genotype, Humans, Linear Models, Microfilament Proteins, Middle Aged, Phenotype, Phosphoproteins, Phosphorylation, Platelet Aggregation Inhibitors, Platelet Function Tests, Polymorphism, Single Nucleotide, Prospective Studies, Receptors, Adrenergic, alpha-2, beta-2, Ticlopidine, Treatment Outcome, Antiplatelet agents, Coronary syndrome, Single nucleotide polymorphisms, Platelet, Receptor, biology, Hematology, Clopidogrel, Enzyme inhibitor, Phosphoprotein, Linear Model, Drug Therapy, Combination, medicine.drug, Acute coronary syndrome, medicine.medical_specialty, Adrenergic receptor, Antiplatelet agent, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Receptors, Adrenergic, alpha-2, Internal medicine, medicine, business.industry, Platelet Aggregation Inhibitor, vasodilator stimulated phosphoprotein, acute coronary syndrome, Microfilament Protein, medicine.disease, Platelet Function Test, Prospective Studie, Endocrinology, Cell Adhesion Molecule, biology.protein, Receptors, Adrenergic, beta-2, business, treatment outcome, Acute Coronary Syndrome
Abstract

SummaryPlatelet response to clopidogrel shows inter-individual variability that is partially explained by genetic polymorphisms. This variability affects clinical outcome when clopidogrel is administered in patients with acute coronary syndrome (ACS). Catecholamines, released during ACS, contribute to platelet aggregation through platelet α2A- (α2A-AR) and β2-adrenergic receptor (β2-AR) stimulation. It was the objective of this study to assess the potential influence of α2A-AR and β2-AR gene polymorphisms on platelet reactivity after dual antiplatelet therapy with aspirin and clopidogrel in ACS. We screened 641 ACS patients for 6.3/6.7 kb α2A-AR polymorphism, and for Arg16Gly and Gln27Glu β2-AR polymorphism. After 600 mg clopidogrel, we assessed ADP 10 μmol-induced platelet aggregation (ADP-Ag) and vasoactive stimulated phosphoprotein (VASP). All single nucleotide polymorphisms were in Hardy-Weinberg equilibrium. A slight though negligible association was found between 6.3 kb allele of α2A-AR with platelet reactivity ADPAg induced (beta: –2.91 [-5.68;-0.14], p=0.04). A borderline not significant reduction in PRI VASP was observed in 6.3 kb α2A-AR carriers (beta: –3.81 [-0.09;7.72], p=0.06). No significant effect on platelet parameters was observed for the other tested polymorphisms. Common α2A- and β2-adrenergic receptor polymorphisms do not show any major impact on residual platelet reactivity in non-ST-elevation ACS when a dual antiplatelet therapy with 250 mg aspirin and 600 mg clopidogrel is administered.

Published
2010

45. C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S-independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies

Author

Alfonso Buil, David-Alexandre Trégouët, Juan Carlos Souto, Noémie Saut, Marine Germain, Maxime Rotival, Laurence Tiret, Françcois Cambien, Mark Lathrop, Tanja Zeller, Marie-Christine Alessi, Santiago Rodriguez de Cordoba, Thomas Münzel, Philipp Wild, Jordi Fontcuberta, France Gagnon, Joseph Emmerich, Laura Almasy, Stefan Blankenberg, José-Manuel Soria, and Pierre-Emmanuel Morange

Subjects
Male, Immunology, Single-nucleotide polymorphism, Genome-wide association study, Locus (genetics), Thrombophilia, Biochemistry, Polymorphism, Single Nucleotide, Protein S, Risk Factors, Histocompatibility Antigens, Medicine, Humans, Genetic Predisposition to Disease, Allele, Genetics, Venous Thrombosis, Clinical Trials as Topic, biology, business.industry, C4b-binding protein, Complement C4b-Binding Protein, Case-control study, Cell Biology, Hematology, medicine.disease, PS-independent, protein (C4BP), Gene Expression Regulation, Genetic Loci, Case-Control Studies, protein S (PS), biology.protein, Female, business, Genome-Wide Association Study
Abstract

3 Figures. 2 Tables. The online version of this article contains a data supplement., Through its binding with protein S (PS), a key element of the coagulation/fibrinolysis cascade, the C4b-binding protein (C4BP) has been hypothesized to be involved in the susceptibility to venous thrombosis (VT). To identify genetic factors that may influence the plasma levels of the 3 C4BP existing isoforms, α7β1, α6β1, and α7β0, we conducted a genome-wide association study by analyzing 283 437 single nucleotide polymorphisms (SNPs) in the Genetic Analysis of Idiopathic Thrombophilia (GAIT) study composed of 352 persons. Three SNPs at the C4BPB/C4BPA locus were found genome-wide significantly associated with α7β0 levels. One of these SNPs was further found to explain approximately 11% of the variability of mRNA C4BPA expression in the Gutenberg Heart Study composed of 1490 persons, with no effect on C4BPB mRNA expression. The allele associated with increased α7β0 plasma levels and increased C4BPA expression was further found associated with increased risk of VT (odds ratio [OR] = 1.24 [1.03-1.53]) in 2 independent case-control studies (MARseille THrombosis Association study [MARTHA] and FActeurs de RIsque et de récidives de la maladie thromboembolique VEineuse [FARIVE]) gathering 1706 cases and 1379 controls. This SNP was not associated with free PS or total PS. In conclusion, we observed strong evidence that the C4BPB/C4BPA locus is a new susceptibility locus for VT through a PS-independent mechanism that remains to be elucidated., National Institutes of Health, PI-08/0420, PI-08/0756, SAF2008/01859, and Spanish Society on Thrombosis and Hemostasia (SETH). The FARIVE study was supported by grants from the Fondation pour la Recherche Médicale, the Program Hospitalier de recherche Clinique, the Fondation de France, and the Leducq Foundation. The MARTHA study was supported by a grant from the Program Hospitalier de la Recherche Clinique. The Gutenberg Heart Study is funded through the government of Rheinland-Pfalz (Stiftung Rheinland Pfalz für Innovation, contract no. AZ 961-386261/733), the research programsWissen schafft Zukunft and Schwerpunkt Vaskula¨re Prävention of the Johannes Gutenberg-University of Mainz and its contract with Boehringer Ingelheim and PHILIPS Medical Systems including an unrestricted grant for the Gutenberg Heart Study. Specifically, the research reported in this article was supported by the National Genome Network NGFNplus (contract no. project A3 01GS0833) by the Federal Ministry of Education and Research, Germany. J.-M.S. was supported by Programa d’Estabilització d’Investigadors de la Direcció d’Estrategia i Coordinació del Departament de Salut (Generalitat de Catalunya); M.G., by a grant funded by the Agence Nationale pour la Recherche (Project ANR-07-MRAR-021). F.G. holds a Canada Research Chair.

Published
2010

46. Polymorphisms of the lamina maturation pathway and their association with the metabolic syndrome: the DESIR prospective study

Author

Anne Dutour, Nicolas Lévy, B. Balkau, Pierre-Emmanuel Morange, Marie-Christine Alessi, Catherine Badens, Michel Marre, Irène Juhan-Vague, Jean Tichet, David-Alexandre Trégouët, Noémie Saut, Bénédicte Fontaine-Bisson, and Frédéric Fumeron

Subjects
Adult, Male, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, LMNA, Drug Discovery, Genotype, medicine, Humans, Genetic Predisposition to Disease, Prospective Studies, Genetics (clinical), Genetic association, Aged, Genetics, Metabolic Syndrome, integumentary system, Haplotype, Proteins, Middle Aged, medicine.disease, Lamin Type A, Human genetics, Lamins, Molecular Medicine, Female, France, Metabolic syndrome, Lamin
Abstract

Laminopathies are rare monogenic diseases, some of them exhibiting features of the metabolic syndrome. These diseases are mainly due to mutations in LMNA, encoding A-type lamins. One LMNA polymorphism, rs4641, has been associated with the metabolic syndrome, but results have been controversial. We therefore investigated the effect of single nucleotide polymorphisms (SNPs) in the LMNA gene in combination with four other genes encoding enzymes influencing lamin post-translational maturation on risk of metabolic syndrome (MS). Twenty-three tagging SNPs characterising the haplotypic variability of five genes (LMNA, ICMT, ZMPSTE24, FNTA and FNTB) were genotyped in 3,916 French men and women who took part in the prospective DESIR study. Single locus and haplotype analyses were performed but did not detect any significant association with the risk of MS. No robust interaction between SNPs located in different genes on the risk of MS was identified. In conclusion, we did not observe any convincing evidence that common polymorphisms of the lamina pathway could modulate the risk of MS.

Published
2009

47. Relation between the antithrombin Cambridge II mutation, the risk of venous thrombosis, and the endogenous thrombin generation

Author

C. Sanchez, M. F. Aillaud, Noémie Saut, Pierre Morange, and Marie-Christine Alessi

Subjects
Adult, Male, Risk, medicine.medical_specialty, Adolescent, Antithrombin III, Endogeny, Thrombin generation, Young Adult, Internal medicine, medicine, Humans, Antithrombin Cambridge II, Child, Family Health, Venous Thrombosis, business.industry, Thrombin, Hematology, Middle Aged, medicine.disease, Venous thrombosis, Endocrinology, Mutation (genetic algorithm), Mutation, Female, France, business
Published
2008

48. TAFI antigen level variability in young healthy Asian Indians; first report from Asia

Author

Madhuri Behari, Renu Saxena, Corinne Frere, Suhail Akhter, Noémie Saut, Arijit Biswas, Ravi Ranjan, Deepak Kumar Shukla, Arvind Meena, and Irene Juhan Vague

Subjects
Adult, Male, Carboxypeptidase B2, Adolescent, medicine.medical_treatment, Coefficient of variation, Clinical Biochemistry, Population, India, Fibrin, Thrombin, Antigen, Asian People, Fibrinolysis, medicine, Humans, education, Child, education.field_of_study, biology, Chemistry, Genetic Variation, General Medicine, Blood proteins, Child, Preschool, Immunology, biology.protein, Fibrinolytic inhibitor, Female, medicine.drug
Abstract

Thrombin Activatable Fibrinolytic Inhibitor (TAFI) is a plasma protein, which inhibits fibrinolysis by removing carboxyterminal lysine residues from partially degraded fibrin thereby decreasing plasminogen binding on its surface. In this study we have investigated the antigenic level variability (Inter and Intraindividual) of Thrombin Activatable Fibrinolysis Inhibitor in 120 healthy Asian Indians since no data on this is available regarding this population. TAFI antigen levels did not show a normal distribution in our population (p0.001). Median TAFI antigen levels were found to be 11.683 microg/ml. It ranged from 33.9-202.5%of normal pool plasma (3.9-23.5 microg/ml). TAFI antigenic level showed high level of variability in the Indian population (coefficient of variation: 37.4%). TAFI antigenic levels were stable intraindividually (p=0.218).

Published
2007

49. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome

Author

Marie-Christine Alessi, Thomas Cuisset, Dorothée Faille, Pierre-Emmanuel Morange, Jacques Quilici, Jean-Louis Bonnet, Irène Juhan-Vague, Corinne Frere, Marc Lambert, Laurence Camoin-Jau, and Noémie Saut

Subjects
Male, Acute coronary syndrome, medicine.medical_specialty, Heterozygote, Ticlopidine, Drug Resistance, CYP2C19, Polymorphism, Single Nucleotide, Body Mass Index, chemistry.chemical_compound, Cytochrome P-450 Enzyme System, Internal medicine, medicine, Humans, Platelet, Platelet activation, Prospective Studies, Acute Coronary Syndrome, Phosphorylation, Alleles, business.industry, Microfilament Proteins, Middle Aged, medicine.disease, Clopidogrel, Phosphoproteins, Platelet Activation, Adenosine Diphosphate, Adenosine diphosphate, P-Selectin, chemistry, Cardiology, Platelet aggregation inhibitor, Female, Cardiology and Cardiovascular Medicine, business, Cell Adhesion Molecules, Platelet Aggregation Inhibitors, medicine.drug
Abstract

Genetic polymorphisms of cytochrome P450 (CYP) isoforms may promote variability in platelet response to clopidogrel. This study was conducted to analyze, in 603 patients with non-ST elevation acute coronary syndromes, the effect of CYP3A4, CYP3A5, and CYP2C19 gene polymorphisms on clopidogrel response and post-treatment platelet reactivity assessed by adenosine diphosphate (ADP)-induced platelet aggregation, vasodilator-stimulated phosphoprotein phosphorylation index, and ADP-induced P-selectin expression. The CYP2C19*2 polymorphism was significantly associated with ADP-induced platelet aggregation, vasodilator-stimulated phosphoprotein phosphorylation index, and ADP-induced P-selectin expression in recessive (p0.01, p0.007, and p0.06, respectively) and codominant (p0.08, p0.0001, and p0.009, respectively) models, but the CYP3A4*1B and CYP3A5*3 polymorphisms were not. The CYP2C19*2 allele carriers exhibited the highest platelet index levels in multivariate analysis (p = 0.03). After covariate adjustment, the CYP2C19*2 allele was more frequent in clopidogrel nonresponders, defined by persistent high post-treatment platelet reactivity (ADP-induced platelet aggregation70%; p = 0.03). In conclusion, the present data suggest that the CYPC19*2 allele influences post-treatment platelet reactivity and clopidogrel response in patients with non-ST elevation acute coronary syndromes.

Published
2007

50. Association of plasminogen activator inhibitor (PAI)-1 (SERPINE1) SNPs with myocardial infarction, plasma PAI-1, and metabolic parameters: the HIFMECH study

Author

Anders Hamsten, S.E. Humphries, John S Yudkin, G. Di Minno, Irène Juhan-Vague, Pierre Morange, Marie-Christine Alessi, Maurizio Margaglione, David-Alexandre Trégouët, Noémie Saut, Morange, Pe, Saut, N, Alessi, Mc, Yudkin, J, Margaglione, M, DI MINNO, Giovanni, Hamsten, A, Humphries, Se, Tregouet, Da, and JUHAN VAGUE, I.

Subjects
Male, medicine.medical_specialty, medicine.medical_treatment, PAI-1, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Risk Assessment, Linkage Disequilibrium, White People, Body Mass Index, chemistry.chemical_compound, Gene Frequency, Risk Factors, Internal medicine, Genetic variation, Plasminogen Activator Inhibitor 1, medicine, Humans, Insulin, Genetic Predisposition to Disease, Risk factor, Promoter Regions, Genetic, Metabolic Syndrome, business.industry, Haplotype, Smoking, Middle Aged, medicine.disease, Europe, Endocrinology, Phenotype, myocardial infarction, chemistry, Haplotypes, Plasminogen activator inhibitor-1, Case-Control Studies, Metabolic syndrome, Cardiology and Cardiovascular Medicine, business, Plasminogen activator, SERPINE1
Abstract

Objective— The purpose of this study was to investigate the effects of plasminogen activator inhibitor-1 (PAI-1) gene (SERPINE1) single nucleotide polymorphisms (SNPs) on the risk of myocardial infarction (MI), on PAI-1 levels, and factors related to the metabolic syndrome. Methods and Results— Eleven SNPs capturing the common genetic variation of the SERPINE1 gene were genotyped in the HIFMECH study. In the 510 male cases and their 543 age-matched controls, a significant gene-smoking interaction was observed. In nonsmokers, the rs7242-G allele was more frequent in cases than in controls (0.486 versus 0.382, P =0.013) whereas the haplotype derived from the rs2227631 (−844A>G)-G and rs2227683-A alleles was ≈3-fold lower in cases than in controls (0.042 versus 0.115, P =0.006). SERPINE1 haplotypes explained 3.5% ( P =0.007) of the variability of PAI-1 levels, which was attributable to the combined effects of 3 SNPs, −844A>G, rs2227666, and rs2227694. The rs6092 (Ala15Thr) and rs7242 SNPs acted additively to explain 4.4% of the variability of plasma insulin levels and 1.6% of the variability of BMI ( P −3 and P =0.023, respectively). Conclusions— SERPINE1 haplotypes are mildly associated with plasma levels of PAI-1 and with the risk of MI in nonsmokers. They are also associated with insulin levels and BMI.

Published
2007

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