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6 results on '"Génétique épidémiologique et moléculaire des pathologies cardiovasculaires"'

1. FLNC pathogenic variants in patients with cardiomyopathies: Prevalence and genotype‐phenotype correlations

Author

Ader, Flavie, De Groote, Pascal, Réant, Patricia, Rooryck-Thambo, Caroline, Dupin-Deguine, Delphine, Rambaud, Caroline, Khraiche, Diala, Perret, Claire, Pruny, Jean François, Mathieu-Dramard, Michele, Gérard, Marion, Troadec, Yann, Gouya, Laurent, Jeunemaitre, Xavier, Van Maldergem, Lionel, Hagège, Albert, Villard, Eric, Charron, Philippe, Richard, Pascale, Rooryck‐Thambo, Caroline, Dupin‐Deguine, Delphine, Mathieu‐Dramard, Michèle, 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], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Sorbonne Université (SU), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], 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), Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Adaptation cardiovasculaire à l'ischemie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Service de génétique médicale, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Stress Abiotiques et Différenciation des Végétaux Cultivés (SADV), Université de Lille, Sciences et Technologies-Institut National de la Recherche Agronomique (INRA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Therapie Cellulaire en Pathologie Cardio-Vasculaire (UMR_S 633), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), gerard, marion, 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), 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], Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National de la Recherche Agronomique (INRA)-Université de Lille, Sciences et Technologies, 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Chrono-environnement - UFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université de Montréal - UdeM (CANADA), Université de Montréal (UdeM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre de Génétique Moléculaire et Chromosomique du GH Pitié-Salpêtrière-CHU Pitié-Salpêtrière [APHP], CHU Pitié-Salpêtrière [APHP], Département de cardiologie, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], Service d'Anatomie Pathologique et Médecine Légale, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital Raymond Poincaré [Garches], 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), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bichat, Université Paris Descartes - Paris 5 (UPD5)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie [CHU HEGP], 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), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Paris - UFR Sciences Fondamentales et Biomédicales [Sciences], Université de Paris (UP), Hôpital Raymond Poincaré [AP-HP], Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de cardiologie [CHU Pitié-Salpêtrière], CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)

Subjects
Male, cardiomyopathies, 0301 basic medicine, Genotype-phenotype correlation, Genotype, Filamins, Cardiomyopathy, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030105 genetics & heredity, Sudden cardiac death, Electrocardiography, 03 medical and health sciences, Prevalence, Genetics, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, Genetic Testing, FLNC, Indel, Alleles, Genetic Association Studies, Genetics (clinical), next generation sequencing, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Genetic Variation, High-Throughput Nucleotide Sequencing, Dilated cardiomyopathy, Sequence Analysis, DNA, medicine.disease, Magnetic Resonance Imaging, Phenotype, Pedigree, 3. Good health, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Echocardiography, Mutation, Female, business, myopathy
Abstract

International audience; Pathogenic variants in FLNC encoding filamin C have been firstly reported to cause myopathies, and were recently linked to isolated cardiac phenotypes. Our aim was to estimate the prevalence of FLNC pathogenic variants in subtypes of cardiomyopathies and to study the relations between phenotype and genotype. DNAs from a cohort of 1150 unrelated index-patients with isolated cardiomyopathy (700 hypertrophic, 300 dilated, 50 restrictive cardiomyopathies, and 100 left ventricle non-compactions) have been sequenced on a custom panel of 51 cardiomyopathy disease-causing genes. An FLNC pathogenic variant was identified in 28 patients corresponding to a prevalence ranging from 1% to 8% depending on the cardiomyopathy subtype. Truncating variants were always identified in patients with dilated cardiomyopathy, while missense or in-frame indel variants were found in other phenotypes. A personal or family history of sudden cardiac death (SCD) was significantly higher in patients with truncating variants than in patients carrying missense variants (P = .01). This work reported the first observation of a left ventricular non-compaction associated with a unique probably causal variant in FLNC which highlights the role of FLNC in cardiomyopathies. A correlation between the nature of the variant and the cardiomyopathy subtype was observed as well as with SCD risk.

Published
2019
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2. Impact of coronary artery disease in patients undergoing transcatheter aortic valve replacement: Insights from the FRANCE-2 registry

Author

Alain Leguerrier, Didier Carrié, Patrick Donzeau-Gouge, Thierry Lefèvre, Stephan Chassaing, Etienne Puymirat, Jean Fajadet, Martine Gillard, Emmanuel Teiger, Pascal Leprince, Hervé Le Breton, Michel Lievre, Eric Durand, Jean-Philippe Collet, Dominique Himbert, Didier Tchetche, Karine Chevreul, Bernard Lung, Hélène Eltchaninoff, Romain Didier, Florence Leclercq, Didier Blanchard, Vascular research center of Marseille (VRCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Département Cardiologie, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de cardiologie [CHU Rouen], Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Service de cardiologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), CHU Rouen, Service de chirurgie thoracique cardiaque et vasculaire [Rennes] = Thoracic and Cardiovascular Surgery [Rennes], CHU Pontchaillou [Rennes], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Clinique Pasteur, Clinique Pasteur [Toulouse], Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Evaluation et modélisation des effets thérapeutiques, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-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 Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-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), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Clinique Saint Gatien, Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cardiovasculaire Paris Sud (ICPS), Optimisation des régulations physiologiques (ORPHY (EA 4324)), Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Edwards Lifesciences, Medtronic, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de chirurgie thoracique cardiaque et vasculaire [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], CHU Pitié-Salpêtrière [APHP], Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Institut de Recherche pour le Développement (IRD [France-Sud])-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)

Subjects
Male, [SDV]Life Sciences [q-bio], medicine.medical_treatment, CAD, Disease, Coronary Artery Disease, 030204 cardiovascular system & hematology, Coronary Angiography, Severity of Illness Index, Coronary artery disease, 0302 clinical medicine, Valve replacement, Risk Factors, Registries, 030212 general & internal medicine, Coronary Artery Bypass, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, education.field_of_study, Incidence, Hazard ratio, General Medicine, 3. Good health, Survival Rate, Treatment Outcome, medicine.anatomical_structure, Aortic Valve, Cardiology, Female, France, Cardiology and Cardiovascular Medicine, Artery, medicine.medical_specialty, Transcatheter aortic, Population, Clinical Investigations, Revascularization, Risk Assessment, Transcatheter Aortic Valve Replacement, 03 medical and health sciences, Percutaneous Coronary Intervention, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Humans, In patient, cardiovascular diseases, education, business.industry, Percutaneous coronary intervention, Aortic Valve Stenosis, medicine.disease, Confidence interval, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

BACKGROUND: Coronary artery disease (CAD) is common in patients undergoing transcatheter aortic valve replacement (TAVR). However, the impact of CAD distribution before TAVR on short‐ and long‐term prognosis remains unclear. HYPOTHESIS: We hypothesized that the long‐term clinical impact differs according to CAD distribution in patients undergoing TAVR using the FRench Aortic National CoreValve and Edwards (FRANCE‐2) registry. METHODS: FRANCE‐2 is a national French registry including all consecutive TAVR performed between 2010 and 2012 in 34 centers. Three‐year mortality was assessed in relation to CAD status. CAD was defined as at least 1 coronary stenosis >50%. RESULTS: A total of 4201 patients were enrolled in the registry. For the present analysis, we excluded patients with a history of coronary artery bypass. CAD was reported in 1252 patients (30%). Half of the patients presented with coronary multivessel disease. CAD extent was associated with an increase in cardiovascular risk profile and in logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) (from 19.3% ± 12.8% to 21.9% ± 13.5%, P < 0.001). Mortality at 30 days and 3 years was 9% and 44%, respectively, in the overall population. In multivariate analyses, neither the presence nor the extent of CAD was associated with mortality at 3 years (presence of CAD, hazard ratio [HR]: 0.90; 95% confidence interval [CI]: 0.78‐1.07). A significant lesion of the left anterior descending (LAD) was associated with higher 3‐year mortality (HR: 1.42; 95% CI: 1.10‐1.87). CONCLUSIONS: CAD is not associated with decreased short‐ and long‐term survival in patients undergoing TAVR. The potential deleterious effect of LAD disease on long‐term survival and the need for revascularization before or at the time of TAVR should be validated in a randomized control trial.

Published
2017
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3. Phospholipolyzed LDL induces an inflammatory response in endothelial cells through endoplasmic reticulum stress signaling

Author

Kristell Wanherdrick, Sonia-Athina Karabina, Gérard Lambeau, Rajai Atout, Ewa Ninio, Seraya Maouche, François Cambien, Sarah Gora, 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), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), and Université Nice Sophia Antipolis (... - 2019) (UNS)

Subjects
Umbilical Veins, Cytoskeleton organization, p38 mitogen-activated protein kinases, Blotting, Western, Eukaryotic Initiation Factor-2, Fluorescent Antibody Technique, Inflammation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Protein Serine-Threonine Kinases, 030204 cardiovascular system & hematology, Biology, Endoplasmic Reticulum, Biochemistry, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Endoribonucleases, Genetics, medicine, Humans, Gene Silencing, Phospholipases A2, Secretory, Molecular Biology, Cells, Cultured, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, 0303 health sciences, Interleukin-6, Reverse Transcriptase Polymerase Chain Reaction, ATF6, Endoplasmic reticulum, Interleukin-8, Endothelial Cells, Activating Transcription Factor 6, 3. Good health, Cell biology, Lipoproteins, LDL, Endothelial stem cell, Unfolded Protein Response, Unfolded protein response, medicine.symptom, Signal Transduction, Biotechnology
Abstract

International audience; Secreted phospholipases A2 (sPLA2s) are present in atherosclerotic plaques and are now considered novel attractive therapeutic targets and potential biomarkers as they contribute to the development of atherosclerosis through lipoprotein-dependent and independent mechanisms. We have previously shown that hGX-sPLA2-phospholipolyzed LDL (LDL-X) induces proinflammatory responses in human umbilical endothelial cells (HUVECs); here we explore the molecular mechanisms involved. Global transcriptional gene expression profiling of the response of endothelial cells exposed to either LDL or LDL-X revealed that LDL-X activates multiple distinct cellular pathways including the unfolded protein response (UPR). Mechanistic insight showed that LDL-X activates UPR through calcium depletion of intracellular stores, which in turn disturbs cytoskeleton organization. Treatment of HUVECs and aortic endothelial cells (HAECs) with LDL-X led to activation of all 3 proximal initiators of UPR: eIF-2alpha, IRE1alpha, and ATF6. In parallel, we observed a sustained phosphorylation of the p38 pathway resulting in the phosphorylation of AP-1 downstream targets. This was accompanied by significant production of the proinflammatory cytokines IL-6 and IL-8. Our study demonstrates that phospholipolyzed LDL uses a range of molecular pathways including UPR to initiate endothelial cell perturbation and thus provides an LDL oxidation-independent mechanism for the initiation of vascular inflammation in atherosclerosis.-Gora, S., Maouche, S., Atout, R., Wanherdrick, K., Lambeau, G., Cambien, F., Ninio, E., Karabina, S.-A. Phospholipolyzed LDL induces an inflammatory response in endothelial cells through endoplasmic reticulum stress signaling.

Published
2010
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4. Genetic susceptibilities in the association between maternal exposure to tobacco smoke and the risk of nonsyndromic oral cleft

Author

Agnès Nelva, Christine Francannet, Sylvaine Cordier, Elisabeth Robert-Gnansia, Claire Perret, Christine Herman, Marie-Paule Vazquez, David M. Iovannisci, Michel Bahuau, Cécile Chevrier, Edward J. Lammer, Groupe d'Etude de la Reproduction Chez l'Homme et les Mammiferes (GERHM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Children's Hospital Oakland Research, Registre des Malformations Rhône-Alpes, REMERA, Centre d'Etude des Malformations Congénitales (CEMC), Centre d'Etude des Malformations Congénitales, Unité de Génétique Médicale, Hôtel-Dieu-CHU Clermont-Ferrand-Université d'Auvergne - Clermont-Ferrand I (UdA), Children's Hospital Oakland Research Institute, hildren's Hospital Oakland Research Institute, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de stomatologie et chirurgie maxillo-faciale [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Forgeron, Christine

Subjects
Male, Passive smoking, Physiology, MESH: Logistic Models, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, Tobacco smoke, MESH: Genotype, MESH: Pregnancy, Pregnancy, Risk Factors, MESH: Risk Factors, Smoke, Medicine, MESH: Maternal Exposure, MESH: Tobacco, Genetics (clinical), Glutathione Transferase, Genetics, 0303 health sciences, education.field_of_study, Smoking, 030305 genetics & heredity, MESH: Genetic Predisposition to Disease, MESH: Smoke, MESH: Case-Control Studies, MESH: Infant, 3. Good health, Cleft Palate, Maternal Exposure, Female, France, MESH: Pregnancy Trimester, First, MESH: Smoking, Genotype, Cleft Lip, Population, Genetic determinism, 03 medical and health sciences, Tobacco, MESH: Polymorphism, Genetic, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Allele, Risk factor, education, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, 030304 developmental biology, MESH: Glutathione Transferase, [SDV.GEN]Life Sciences [q-bio]/Genetics, Polymorphism, Genetic, MESH: Humans, business.industry, MESH: Cleft Lip, Infant, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, medicine.disease, MESH: Male, MESH: France, Pregnancy Trimester, First, Logistic Models, MESH: Cleft Palate, Case-Control Studies, Relative risk, business, MESH: Female
Abstract

International audience; Maternal tobacco consumption is considered as a risk factor for nonsyndromic oral clefts. However, this risk is moderate and may be modulated by genetic susceptibilities, including variants of the TGFA, TGFB3 and MSX1 developmental genes and polymorphisms of genes of the CYP (1A1, 2E1) and GST (M1, T1) families involved in metabolic pathways of tobacco smoke compounds. This French case-control study (1998-2001; 240 nonsyndromic cases, 236 controls) included a case-parent design (175 triad-families) that made it possible to distinguish the direct effect of the child's genotype and maternally mediated effects. Maternal smoking during the first trimester of pregnancy was not associated with the oral cleft risk in this population, but we observed statistically significant increased risks associated with maternal exposure to environmental tobacco smoke (ETS). No variant of any of the three developmental genes was significantly associated with oral cleft. The fetal CYP1A1*2C variant allele was associated with a statistically significant decreased risk, compared with the homozygous wild-type: relative risk = 0.48, 95% confidence interval: 0.2, 1.0. Suggestive reduced risks were also observed for the maternal CYP1A1*2C allele and the fetal CYP2E1*5 allele. The GSTM1 and GSTT1 deletions appeared to play no role. Our findings suggest some interactions, with the strongest between ETS and CYP1A1 or MSX1 and between maternal smoking and CYP2E1. We did not confirm the maternal smoking-infant GSTT1 null interaction previously reported by other investigators.

Published
2008
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5. Fetal and maternalMTHFR C677T genotype, maternal folate intake and the risk of nonsyndromic oral clefts

Author

Sylvaine Cordier, Huiping Zhu, Elisabeth Robert-Gnansia, Christine Francannet, Agnès Nelva, Michel Bahuau, Richard H. Finnell, Cécile Chevrier, Claire Perret, Christine Herman, Groupe d'Etude de la Reproduction Chez l'Homme et les Mammiferes (GERHM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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), Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Registre des Malformations Rhône-Alpes, REMERA, Centre d'Etude des Malformations Congénitales (CEMC), Centre d'Etude des Malformations Congénitales, Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
cleft lip, MESH: Genotype, MESH: Pregnancy, Pregnancy, Polymorphism (computer science), Genotype, Medicine, Genetics (clinical), cleft palate, 0303 health sciences, biology, 030305 genetics & heredity, vitamin, MESH: Genetic Predisposition to Disease, MESH: Methylenetetrahydrofolate Reductase (NADPH2), MESH: Case-Control Studies, 3. Good health, MESH: Maternal Nutritional Physiological Phenomena, nutrition, Female, medicine.medical_specialty, MESH: Mutation, Offspring, folate, MESH: Folic Acid, folic acid, 03 medical and health sciences, MESH: Diet, Internal medicine, MESH: Polymorphism, Genetic, Genetics, Humans, Genetic Predisposition to Disease, Risk factor, Methylenetetrahydrofolate Reductase (NADPH2), 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Polymorphism, Genetic, MESH: Humans, business.industry, MESH: Cleft Lip, Case-control study, Maternal Nutritional Physiological Phenomena, Odds ratio, medicine.disease, methylenetetrahydrofolate reductase, Diet, Endocrinology, MESH: Cleft Palate, Case-Control Studies, Methylenetetrahydrofolate reductase, Mutation, biology.protein, business, MESH: Female
Abstract

International audience; The association between maternal folate intake and risk of nonsyndromic oral clefts has been studied among many populations with conflicting results. The methylenetetrahydrofolate reductase gene (MTHFR) plays a major role in folate metabolism, and several polymorphisms, including C677T, are common in European populations. Data from a French study (1998-2001) let us investigate the roles of maternal dietary folate intake and the MTHFR polymorphism and their interaction on the risk of cleft lip with/without cleft palate (CL/P) and cleft palate only (CP). We used both case-control (164 CL/P, 76 CP, 236 controls; 148, 59, 168 of whom, respectively, had an available genotype) and case-parent (143 CL/P and 56 CP families) study designs and distinguished the role of the child's genotype and maternally mediated effects on risks. This study observed a beneficial effect of mothers' dietary folate intake on their offspring's risk (odds ratio (OR)(< or = 230 microg/day) = ref; for CL/P, OR([230-314 microg/day]) = 0.56, 95% confidence interval = 0.3-0.9, OR(>314 microg/day) = 0.64, 0.4-1.1; for CP, OR([230-314 microg/day]) = 1.15, 0.6-2.2, OR(>314 microg/day) = 0.70, 0.3-1.4). We observed a reduced risk associated with the TT genotype of the child in the case-control analysis (OR(CC) = ref; for CL/P, OR(TT) = 0.54, 0.3-1.1; for CP, OR(TT) = 0.33, 0.1-1.0); this genotype, either fetal or maternal, was not statistically significant in the case-parent analysis. A frequency of TT genotype higher in our control group than previously reported in France can partly explain the risk reduction observed in case-control comparison. Interactions were not statistically significant. Stratified case-parent analysis showed, however, slight heterogeneity in the role of TT genotype according to folate intake. The modest sample size limits this study, which nonetheless provides new estimate of the possible impact of dietary folate intake and MTHFR polymorphism on oral clefts.

Published
2007
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6. Acetylation of TAFI68, a subunit of TIF-IB/SL1, activates RNA polymerase I transcription

Author

Sophie Nadaud, Viola Muth, Renate Voit, Ingrid Grummt, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, and Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Saccharomyces cerevisiae Proteins, Transcription, Genetic, [SDV]Life Sciences [q-bio], Response element, Hydroxamic Acids, DNA, Ribosomal, Gene Expression Regulation, Enzymologic, Histone Deacetylases, Article, General Biochemistry, Genetics and Molecular Biology, Mice, Sirtuin 2, Sp3 transcription factor, Acetyltransferases, RNA Polymerase I, Animals, Sirtuins, Gene Silencing, Molecular Biology, Silent Information Regulator Proteins, Saccharomyces cerevisiae, Histone Acetyltransferases, Terminator Regions, Genetic, General Immunology and Microbiology, biology, General transcription factor, General Neuroscience, TATA-Box Binding Protein, Acetylation, Promoter, Histone acetyltransferase, Molecular biology, Recombinant Proteins, DNA-Binding Proteins, Protein Subunits, TAF2, Trans-Activators, biology.protein, Transcription factor II D, Pol1 Transcription Initiation Complex Proteins, Protein Binding, Transcription Factors
Abstract

International audience; Mammalian rRNA genes are preceded by a terminator element that is recognized by the transcription termination factor TTF-I. In exploring the functional significance of the promoter-proximal terminator, we found that TTF-I associates with the p300/CBP-associated factor PCAF, suggesting that TTF-I may target histone acetyltransferase to the rDNA promoter. We demonstrate that PCAF acetylates TAF(I)68, the second largest subunit of the TATA box-binding protein (TBP)-containing factor TIF-IB/SL1, and acetylation enhances binding of TAF(I)68 to the rDNA promoter. Moreover, PCAF stimulates RNA polymerase I (Pol I) transcription in a reconstituted in vitro system. Consistent with acetylation of TIF-IB/SL1 being required for rDNA transcription, the NAD(+)-dependent histone deacetylase mSir2a deacetylates TAF(I)68 and represses Pol I transcription. The results demonstrate that acetylation of the basal Pol I transcription machinery has functional consequences and suggest that reversible acetylation of TIF-IB/SL1 may be an effective means to regulate rDNA transcription in response to external signals.

Published
2001
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