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7 results on '"Centre de Ressources et de Compétences en Mucoviscidose [CHU Toulouse] (CRCM Toulouse)"'

1. Blood co-expression modules identify potential modifier genes of diabetes and lung function in cystic fibrosis

Author

Pineau, Fanny, Caimmi, Davide, Magalhães, Milena, Fremy, Enora, Mohamed, Abdillah, Mely, Laurent, Leroy, Sylvie, Murris, Marlene, Claustres, Mireille, Chiron, Raphaël, De Sario, Albertina, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centres de Ressources et de Compétences de la Mucoviscidose [Montpellier] (CRCM [Montpellier]), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve-Service des Maladies Respiratoires, Centre de Ressources et de Compétences en Mucoviscidose [Lyon] (CRCM [Lyon]), Hospices Civils de Lyon (HCL)-CHU Lyon-Hôpital Renée Sabran [CHU - HCL], Hospices Civils de Lyon (HCL), Centre de Ressources et de Compétences en Mucoviscidose [Nice] (CRCM [Nice]), Les Hôpitaux Pédiatriques de Nice CHU-Lenval, Centre de Ressources et de Compétences en Mucoviscidose [Toulouse] (CRCM [Toulouse]), CHU Toulouse [Toulouse]-Hôpital Larrey [Toulouse], CHU Toulouse [Toulouse], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), DE SARIO, Albertina, Centre de Ressources et de Compétences en Mucoviscidose [CHU Toulouse] (CRCM Toulouse), Service Pneumologie et allergologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Enfants [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
Male, Cystic Fibrosis, Pulmonology, [SDV]Life Sciences [q-bio], Cystic Fibrosis Transmembrane Conductance Regulator, Pulmonary Function, Gene Expression, Comorbidity, Pathology and Laboratory Medicine, White Blood Cells, Endocrinology, Animal Cells, Medicine and Health Sciences, Lung, Gene Ontologies, Pseudomonas Aeruginosa, Genomics, Bacterial Pathogens, [SDV] Life Sciences [q-bio], Genetic Diseases, Medical Microbiology, Medicine, Female, Pathogens, Cellular Types, Research Article, Adult, Cell Binding, Cell Physiology, Endocrine Disorders, Science, Immune Cells, Immunology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Microbiology, Autosomal Recessive Diseases, Pseudomonas, Diabetes Mellitus, Genetics, Humans, Pseudomonas Infections, Microbial Pathogens, Clinical Genetics, Genes, Modifier, Blood Cells, Bacteria, Organisms, Biology and Life Sciences, Computational Biology, Cell Biology, Genome Analysis, Fibrosis, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Metabolic Disorders, Mutation, Transcriptome, Developmental Biology
Abstract

International audience; Cystic fibrosis (CF) is a rare genetic disease that affects the respiratory and digestive systems. Lung disease is variable among CF patients and associated with the development of comorbidities and chronic infections. The rate of lung function deterioration depends not only on the type of mutations in CFTR, the disease-causing gene, but also on modifier genes. In the present study, we aimed to identify genes and pathways that (i) contribute to the pathogenesis of cystic fibrosis and (ii) modulate the associated comorbidities. We profiled blood samples in CF patients and healthy controls and analyzed RNA-seq data with Weighted Gene Correlation Network Analysis (WGCNA). Interestingly, lung function, body mass index, the presence of diabetes, and chronic P. aeruginosa infections correlated with four modules of co-expressed genes. Detailed inspection of networks and hub genes pointed to cell adhesion, leukocyte trafficking and production of reactive oxygen species as central mechanisms in lung function decline and cystic fibrosis-related diabetes. Of note, we showed that blood is an informative surrogate tissue to study the contribution of inflammation to lung disease and diabetes in CF patients. Finally, we provided evidence that WGCNA is useful to analyze-omic datasets in rare genetic diseases as patient cohorts are inevitably small.

Published
2020

2. Dynamic changes of DNA methylation and lung disease in cystic fibrosis: lessons from a monogenic disease

Author

Nathan Alary, Laurent Mely, Florence Busato, Milena Magalhães, Sylvie Leroy, Fanny Pineau, Isabelle Rivals, Raphaël Chiron, Albertina De Sario, Jörg Tost, Davide Caimmi, M. Murris, Mireille Claustres, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Epigénétique et d'Environnement [Evry] (CNG - CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de Genotypage-Institut de Génomique [Evry], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Equipe de Statistique Appliquée (UMRS 1158) (ESA), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de Ressources et de Compétences en Mucoviscidose [Lyon] (CRCM [Lyon]), Hospices Civils de Lyon (HCL)-CHU Lyon-Hôpital Renée Sabran [CHU - HCL], Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre de Ressources et de Compétences en Mucoviscidose [Toulouse] (CRCM [Toulouse]), CHU Toulouse [Toulouse]-Hôpital Larrey [Toulouse], CHU Toulouse [Toulouse], Centres de Ressources et de Compétences de la Mucoviscidose [Montpellier] (CRCM [Montpellier]), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve-Service des Maladies Respiratoires, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Ressources et de Compétences en Mucoviscidose [CHU Toulouse] (CRCM Toulouse), Service Pneumologie et allergologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Enfants [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
Adult, Male, 0301 basic medicine, Cancer Research, [SDV]Life Sciences [q-bio], Gene Expression, Nose, Biology, Cystic fibrosis, cystic fibrosis, 03 medical and health sciences, Immune system, Genetics, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Enhancer, Gene, ComputingMilieux_MISCELLANEOUS, epigenetics and disease, DNA methylation, Lung, Epithelial Cells, medicine.disease, Phenotype, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, CpG site, Cancer research, CpG Islands, Female
Abstract

Aim: To assess whether DNA methylation levels account for the noninherited phenotypic variations observed among cystic fibrosis (CF) patients. Patients & methods: Using the 450 K BeadChip, we profiled DNA methylation in nasal epithelial cells collected from 32 CF patients and 16 controls. Results: We detected substantial DNA methylation differences up to 55% (median β change 0.13; IQR: 0.15–0.11) between CF patients and controls. DNA methylation levels differed between mild and severe CF patients and correlated with lung function at 50 CpG sites. Conclusion: In CF samples, dynamic changes of DNA methylation occurred in genes responsible for the integrity of the epithelium and the inflammatory and immune responses, were prominent in transcriptionally active genomic regions and were over-represented in enhancers active in lung tissues. ( Clinicaltrials.gov NCT02884622).

Published
2018

3. Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis

Author

Pierre-Régis Burgel, Anne Munck, Isabelle Durieu, Raphaël Chiron, Laurent Mely, Anne Prevotat, Marlene Murris-Espin, Michele Porzio, Michel Abely, Philippe Reix, Christophe Marguet, Julie Macey, Isabelle Sermet-Gaudelus, Harriet Corvol, Stéphanie Bui, Lydie Lemonnier, Clémence Dehillotte, Jennifer Da Silva, Jean-Louis Paillasseur, Dominique Hubert, Julie Mounard, Claire Poulet, Cinthia Rames, Christine Person, Françoise Troussier, Thierry Urban, Marie-Laure Dalphin, Jean-Claude Dalphin, Didier Pernet, Bénédicte Richaud-Thiriez, Mickael Fayon, Julie Macey-Caro, Karine Campbell, Muriel Laurans, Corinne Borderon, Marie-Christine Heraud, André Labbé, Sylvie Montcouquiol, Laurence Bassinet, Natascha Remus, Annlyse Fanton, Anne Houzel-Charavel, Frédéric Huet, Stéphanie Perez-Martin, Amale Boldron-Ghaddar, Manuela Scalbert, Boubou Camara, Catherine Llerena, Isabelle Pin, Sébastien Quétant, Aurélie Cottereau, Antoine Deschildre, Alice Gicquello, Thierry Perez, Lidwine Stervinou-Wemeau, Caroline Thumerelle, Benoit Wallaert, Nathalie Wizla, Jane Languepin, Céline Ménétrey, Magalie Dupuy-Grasset, Lucie Bazus, Clelia Buchs, Virginie Jubin, Marie-Christine Werck-Gallois, Catherine Mainguy, Thomas Perrin, Agnès Toutain-Rigolet, Stéphane Durupt, Quitterie Reynaud, Raphaele Nove-Josserand, Melisande Baravalle-Einaudi, Bérangère Coltey, Nadine Dufeu, Jean-Christophe Dubus, Nathalie Stremler, Davide Caimmi, Yves Billon, Jocelyne Derelle, Sébastien Kieffer, Anne-Sophie Pichon, Cyril Schweitzer, Aurélie Tatopoulos, Sarah Abbes, Tiphaine Bihouée, Isabelle Danner-Boucher, Valérie David, Alain Haloun, Adrien Tissot, Sylvie Leroy, Carole Bailly-Piccini, Annick Clément, Aline Tamalet, Isabelle Honoré, Reem Kanaan, Clémence Martin, Cécile Bailly, Frédérique Chédevergne, Jacques De Blic, Brigitte Fauroux, Murielle Le Bourgeois, Bertrand Delaisi, Michèle Gérardin, Michel Abély, Bruno Ravoninjatovo, Chantal Belleguic, Benoit Desrues, Graziella Brinchault, Michel Dagorne, Eric Deneuville, Sylvaine Lefeuvre, Anne Dirou, Jean Le Bihan, Sophie Ramel, Stéphane Dominique, Annabelle Payet, Romain Kessler, Vincent Rosner, Laurence Weiss, Sandra de Miranda, Dominique Grenet, Abdoul Hamid, Clément Picard, François Brémont, Alain Didier, Géraldine Labouret, Marie Mittaine, Marlène Murris-Espin, Laurent Têtu, Laure Cosson, Charlotte Giraut, Anne-Cécile Henriet, Julie Mankikian, Sophie Marchand, Sandrine Hugé, Véronique Storni, Emmanuelle Coirier-Duet, CHU Cochin [AP-HP], Service de Médecine Interne - Centre Hospitalier Lyon Sud, Hospices Civils de Lyon (HCL)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de Ressources et de Compétences en Mucoviscidose [Lyon] (CRCM [Lyon]), Hospices Civils de Lyon (HCL)-CHU Lyon-Hôpital Renée Sabran [CHU - HCL], Hôpital Albert Calmette, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Toulouse [Toulouse], 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), Service de pédiatrie médicale et médecine de l'adolescent [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de pneumologie [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Centre de Ressources et de Compétences de la Mucoviscidose (CRCM), Hôpital des Enfants, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Association Vaincre La Mucoviscidose, Institut Cochin (IC UM3 (UMR 8104 / U1016)), EFFI-STAT, CIC Cochin Pasteur (CIC 1417), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Mucoviscidose: physiopathologie et phénogénomique [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Centre de Ressources et de Compétences en Mucoviscidose [CHU Toulouse] (CRCM Toulouse), Service Pneumologie et allergologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-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) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe hospitalier Broca-Université Paris Descartes - Paris 5 (UPD5)-Hôtel-Dieu-Hôpital Cochin [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, Cystic Fibrosis, Gastrointestinal Diseases, [SDV]Life Sciences [q-bio], Aminopyridines, Quinolones, Critical Care and Intensive Care Medicine, Logistic regression, Aminophenols, Cystic fibrosis, Body Mass Index, Ivacaftor, chemistry.chemical_compound, 0302 clinical medicine, Deprescriptions, Forced Expiratory Volume, Medicine, 030212 general & internal medicine, Fatigue, 2. Zero hunger, biology, Lumacaftor, Headache, lumacaftor–ivacaftor, Cystic fibrosis transmembrane conductance regulator, 3. Good health, Anti-Bacterial Agents, Drug Combinations, Treatment Outcome, Administration, Intravenous, Female, France, medicine.drug, Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, Metrorrhagia, Adolescent, Nutritional Status, 03 medical and health sciences, Young Adult, Internal medicine, Product Surveillance, Postmarketing, Humans, Benzodioxoles, Adverse effect, Bronchial Spasm, business.industry, Editorials, Myalgia, medicine.disease, Discontinuation, Dyspnea, Logistic Models, 030228 respiratory system, chemistry, Cough, Multivariate Analysis, biology.protein, postmarketing study, business, Body mass index
Abstract

International audience; Rationale: Lumacaftor-ivacaftor is a CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination recently approved for patients with cystic fibrosis (CF) homozygous for the Phe508del mutation.Objectives: To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life postapproval setting.Methods: The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society's recommendations.Measurements and Main Results: Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV1 (ppFEV1) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV1 (+3.67%), an increase in body mass index (+0.73 kg/m2), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV1, without improvement in body mass index or decrease in intravenous antibiotic courses.Conclusions: Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.

Published
2019

4. Intestinal Inflammation in Children with Cystic Fibrosis Is Associated with Crohn's-Like Microbiota Disturbances

Author

Patrick Berger, Thomas Bazin, Thierry Lamireau, Christophe Hubert, Michael Fayon, Thomas Barnetche, Thierry Schaeverbeke, Laurence Delhaes, H. Clouzeau, Katarzyna B. Hooks, Aurélien Barré, Philippe Lehours, Cécile Bébéar, Stéphanie Bui, Macha Nikolski, Raphaël Enaud, Marie Massot, Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique de Bordeaux (CBIB), CGFB, Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), CHU Bordeaux [Bordeaux], Laboratoire Hubert Curien [Saint Etienne] (LHC), Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS)-Institut d'Optique Graduate School (IOGS), Biodiversité, Gènes & Communautés (BioGeCo), Institut National de la Recherche Agronomique (INRA)-Université de Bordeaux (UB), USC EA 3671, infections humaines à mycoplasmes et chlamydiae, Université de Bordeaux (UB)-Institut National de la Recherche Agronomique (INRA), Centre de Ressources et de Compétences de la Mucoviscidose (CRCM), Hôpital des Enfants, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Service de Pneumologie Pédiatrique [Bordeaux], Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Centre d'Investigation Clinique (CIC 0005), Infection à helicobacter, inflammation et cancer, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU de Bordeaux Pellegrin [Bordeaux], Service de Parasitologie et de Mycologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2, Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS), Institut d'Optique Graduate School (IOGS)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Centre de Ressources et de Compétences en Mucoviscidose [CHU Toulouse] (CRCM Toulouse), Service Pneumologie et allergologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Hooks, Katarzyna

Subjects
0301 basic medicine, dysbiosis index, Faecalibacterium prausnitzii, lcsh:Medicine, Inflammation, Gut flora, Cystic fibrosis, digestive system, Article, cystic fibrosis, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, 0302 clinical medicine, fluids and secretions, intestinal inflammation, Medicine, Veillonella dispar, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, biology, gut microbiota, business.industry, fecal calprotectin, lcsh:R, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, General Medicine, biology.organism_classification, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, stomatognathic diseases, 030104 developmental biology, Immunology, 030211 gastroenterology & hepatology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Bacteroides, medicine.symptom, Calprotectin, business, Dysbiosis
Abstract

Cystic fibrosis (CF) is a systemic genetic disease that leads to pulmonary and digestive disorders. In the majority of CF patients, the intestine is the site of chronic inflammation and microbiota disturbances. The link between gut inflammation and microbiota dysbiosis is still poorly understood. The main objective of this study was to assess gut microbiota composition in CF children depending on their intestinal inflammation. We collected fecal samples from 20 children with CF. Fecal calprotectin levels were measured and fecal microbiota was analyzed by 16S rRNA sequencing. We observed intestinal inflammation was associated with microbiota disturbances characterized mainly by increased abundances of Staphylococcus, Streptococcus, and Veillonella dispar, along with decreased abundances of Bacteroides, Bifidobacterium adolescentis, and Faecalibacterium prausnitzii. Those changes exhibited similarities with that of Crohn&rsquo, s disease (CD), as evidenced by the elevated CD Microbial-Dysbiosis index that we applied for the first time in CF. Furthermore, the significant over-representation of Streptococcus in children with intestinal inflammation appears to be specific to CF and raises the issue of gut&ndash, lung axis involvement. Taken together, our results provide new arguments to link gut microbiota and intestinal inflammation in CF and suggest the key role of the gut&ndash, lung axis in the CF evolution.

Published
2019

5. Carriage of a Single Strain of Nontoxigenic Corynebacterium diphtheriae bv. Belfanti ( Corynebacterium belfantii ) in Four Patients with Cystic Fibrosis

Author

Frédéric Huet, K. Astruc, Marion Benouachkou, Catherine Neuwirth, Diane Pivot, Annlyse Fanton, Alexis Criscuolo, Serge Aho, Julie Toubiana, Edgar Badell-Ocando, Lucie Amoureux, Sylvain Brisse, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de Ressources et de Compétences en Mucoviscidose [CHU Toulouse] (CRCM Toulouse), Service Pneumologie et allergologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, Institut Pasteur [Paris] (IP), Centre national de Référence des Corynebactéries du Complexe Diphtheriae - National Reference Center Corynebacteria of the diphtheriae complex (CNR), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported financially by Dijon University Hospital, Institut Pasteur, and Public Health France., We acknowledge the help of Melody Dazas and Annick Carmi-Leroy for the microbiological characterization of the isolates. We thank the 'Plateforme de Microbiologie Mutualisée' from Institut Pasteur for genomic sequencing, Centre de Ressources et de Compétences de la Mucoviscidose (CRCM), Hôpital des Enfants, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Institut Pasteur [Paris], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Microbiology (medical), MESH: Cystic Fibrosis, Biovar, [SDV]Life Sciences [q-bio], Corynebacterium, MESH: Asymptomatic Infections, Cystic fibrosis, Microbiology, cystic fibrosis, 03 medical and health sciences, MESH: Corynebacterium diphtheriae, MESH: Anti-Bacterial Agents, medicine, Colonization, MESH: Diphtheria, 030304 developmental biology, Corynebacterium diphtheriae, 0303 health sciences, Corynebacterium diphtheriae bv. belfanti, MESH: Humans, biology, 030306 microbiology, business.industry, transmission, MESH: Adult, Antimicrobial, biology.organism_classification, medicine.disease, colonization, MESH: Male, 3. Good health, MESH: France, Carriage, genomic sequencing, epidemiology, business, MESH: Whole Genome Sequencing, MESH: Female
Abstract

International audience; Cystic fibrosis (CF) patients are commonly colonized by bacterial pathogens, which can induce persistent lung inflammation and may contribute to clinical deterioration. Colonization of CF patients and cross-transmission by Corynebacterium diphtheriae have not been reported so far. The aim of this article was to investigate the possibility of a cross-transmission of C. diphtheriae biovar Belfanti between four patients of a CF center. C. diphtheriae biovar Belfanti (now formally called C. belfantii) isolates were collected from four patients in a single CF care center over a period of 6 years and analyzed by microbiological methods and whole-genome sequencing. Epidemiological links among patients were investigated. Ten isolates were collected from 4 patients. Whole-genome sequencing of one isolate from each patient showed that a single strain was shared among them. In addition, one patient was found to have the same strain in two consecutive samplings performed 9 months apart. The strain was nontoxigenic and was susceptible to most antimicrobial agents. Ciprofloxacin resistance was observed in one patient. The idea of transmission of the strain among patients was supported by the occurrence of same-day visits to the CF center. This study demonstrated colonization of CF patients by C. diphtheriae biovar Belfanti (C. belfantii), and the data suggest persistence and transmission of a unique strain during at least 6 years in a single CF patient care center.

Published
2019

6. DNA methylation at modifier genes of lung disease severity is altered in cystic fibrosis

Author

Isabelle Rivals, Anne Bergougnoux, Mélodie Thomasset, Mireille Claustres, Sylvie Leroy, Davide Caimmi, Emmanuelle Beyne, M. Murris, Raphaël Chiron, Isabelle Vachier, Laurent Mely, Harriet Corvol, Jessica Varilh, Albertina De Sario, Milena Magalhães, Loïc Guillot, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Equipe de Statistique Appliquée (UMRS 1158) (ESA), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Ressources et de Compétences en Mucoviscidose [Lyon] (CRCM [Lyon]), Hospices Civils de Lyon (HCL)-CHU Lyon-Hôpital Renée Sabran [CHU - HCL], Hospices Civils de Lyon (HCL), Centre de Ressources et de Compétences en Mucoviscidose [Nice] (CRCM [Nice]), Les Hôpitaux Pédiatriques de Nice CHU-Lenval, Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Ressources et de Compétences en Mucoviscidose [Toulouse] (CRCM [Toulouse]), CHU Toulouse [Toulouse]-Hôpital Larrey [Toulouse], CHU Toulouse [Toulouse], Centres de Ressources et de Compétences de la Mucoviscidose [Montpellier] (CRCM [Montpellier]), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve-Service des Maladies Respiratoires, The project was funded by VLM, INSERM, and Montpellier Hospital. MM was supported by the Ciência Sem Fronteiras Program (CNPq, Brazil) and EB by CHU Montpellier. The FrGMC cohort was supported by INSERM, APHP, UPMC Univ Paris 06, ANR (R09186DS), DGS, VLM, and AICM., Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Mucoviscidose: physiopathologie et phénogénomique [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Pneumologie pédiatrique [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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Centre de Ressources et de Compétences en Mucoviscidose [CHU Toulouse] (CRCM Toulouse), Service Pneumologie et allergologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and BMC, BMC

Subjects
0301 basic medicine, Epigenomics, Lung Diseases, Male, [SDV]Life Sciences [q-bio], Cystic Fibrosis Transmembrane Conductance Regulator, Cystic fibrosis, Severity of Illness Index, Nasal epithelial cells, Co-methylation, Genetics (clinical), Glutathione Transferase, Sequence Deletion, DNA methylation, biology, Pyrosequencing, Environmental exposure, Receptor, Endothelin A, Cystic fibrosis transmembrane conductance regulator, 3. Good health, [SDV] Life Sciences [q-bio], Female, Adult, Pulmonary function, Nose, 03 medical and health sciences, Young Adult, Genetics, medicine, Humans, Allele, Polymorphism, Molecular Biology, Gene, Modifier gene, Genes, Modifier, Research, Epigenome, Sequence Analysis, DNA, medicine.disease, Molecular biology, 030104 developmental biology, Cancer research, biology.protein, Next-generation sequencing, Heme Oxygenase-1, Developmental Biology
Abstract

Background Lung disease progression is variable among cystic fibrosis (CF) patients and depends on DNA mutations in the CFTR gene, polymorphic variations in disease modifier genes, and environmental exposure. The contribution of genetic factors has been extensively investigated, whereas the mechanism whereby environmental factors modulate the lung disease is unknown. In this project, we hypothesized that (i) reiterative stress alters the epigenome in CF-affected tissues and (ii) DNA methylation variations at disease modifier genes modulate the lung function in CF patients. Results We profiled DNA methylation at CFTR, the disease-causing gene, and at 13 lung modifier genes in nasal epithelial cells and whole blood samples from 48 CF patients and 24 healthy controls. CF patients homozygous for the p.Phe508del mutation and ≥18-year-old were stratified according to the lung disease severity. DNA methylation was measured by bisulfite and next-generation sequencing. The DNA methylation profile allowed us to correctly classify 75% of the subjects, thus providing a CF-specific molecular signature. Moreover, in CF patients, DNA methylation at specific genes was highly correlated in the same tissue sample. We suggest that gene methylation in CF cells may be co-regulated by disease-specific trans-factors. Three genes were differentially methylated in CF patients compared with controls and/or in groups of pulmonary severity: HMOX1 and GSTM3 in nasal epithelial samples; HMOX1 and EDNRA in blood samples. The association between pulmonary severity and DNA methylation at EDNRA was confirmed in blood samples from an independent set of CF patients. Also, lower DNA methylation levels at GSTM3 were associated with the GSTM3*B allele, a polymorphic 3-bp deletion that has a protective effect in cystic fibrosis. Conclusions DNA methylation levels are altered in nasal epithelial and blood cell samples from CF patients. Analysis of CFTR and 13 lung disease modifier genes shows DNA methylation changes of small magnitude: some of them are a consequence of the disease; other changes may result in small expression variations that collectively modulate the lung disease severity. Electronic supplementary material The online version of this article (doi:10.1186/s13148-016-0300-8) contains supplementary material, which is available to authorized users.

Published
2016

7. The CF-CIRC study: a French collaborative study to assess the accuracy of Cystic Fibrosis diagnosis in neonatal screening

Author

Aleksander Edelman, Philippe Reix, Stéphanie Bui, E. Deneuville, F. Huet, Gérard Lenoir, Delphine Roussel, Gabriel Bellon, Isabelle Sermet-Gaudelus, Service de pédiatrie générale [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), Régulation des systèmes de transport dans les épithéliums (UMR_S467), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Ressources et de Compétences en Mucoviscidose [CHU Toulouse] (CRCM Toulouse), Service Pneumologie et allergologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Ressources et de Compétences de la Mucoviscidose, hôpital Sud, Hôpital d'Enfants du Bocage, Centre de Ressources et de compétences de la mucoviscidose (CRCM), Hôpital Debrousse, Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Supported by Assistance Publique des Hôpitaux de Paris, Vaincre La Mucoviscidose and ABCF Protéines Associations., Edelman, Aleksander, Centre de Ressources et de Compétences de la Mucoviscidose (CRCM), Hôpital des Enfants, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Sud, and Hospices Civils de Lyon (HCL) - Hospices Civils de Lyon (HCL)

Subjects
Male, Pathology, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Mucous membrane of nose, MESH : Equipment Design, MESH : Child, Preschool, MESH: Catheterization, medicine.disease_cause, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Cystic fibrosis, Gastroenterology, MESH: Amiloride, Amiloride, Study Protocol, MESH : Catheterization, MESH: Genetic Screening, Subcutaneous Tissue, 0302 clinical medicine, MESH : Electric Conductivity, Reference Values, MESH : Chlorides, MESH : Female, 030212 general & internal medicine, Sympathomimetics, Sweat, MESH: Cystic Fibrosis Transmembrane Conductance Regulator, Mutation, biology, medicine.diagnostic_test, lcsh:RJ1-570, MESH : Infant, Equipment Design, MESH: Infant, Cystic fibrosis transmembrane conductance regulator, Electrodes, Implanted, 3. Good health, Perfusion, Research Design, Child, Preschool, Chloride channel, Female, France, Sodium Channel Blockers, MESH: Infant, Newbo, medicine.medical_specialty, MESH : Electrodes, Implanted, MESH: Cystic Fibrosis, MESH: Electric Conductivity, Sensitivity and Specificity, Catheterization, 03 medical and health sciences, MESH : Amiloride, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Neonatal Screening, Chlorides, Predictive Value of Tests, MESH : Cystic Fibrosis, 030225 pediatrics, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Immunoreactive trypsinogen, Pediatrics, Perinatology, and Child Health, Genetic Testing, MESH: Chlorides, MESH : France, Genetic testing, MESH : Genetic Screening, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Newborn screening, MESH: Humans, Ion Transport, business.industry, MESH : Cystic Fibrosis Transmembrane Conductance Regulator, MESH : Humans, MESH: Child, Preschool, Sodium, Electric Conductivity, Infant, Newborn, Isoproterenol, Infant, lcsh:Pediatrics, medicine.disease, MESH: France, Nasal Mucosa, MESH : Infant, Newbo, Pediatrics, Perinatology and Child Health, biology.protein, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, MESH: Electrodes, Implanted, business, MESH: Female, MESH: Equipment Design
Abstract

Background Cystic fibrosis (CF) is caused by mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR) protein, which acts as a chloride channel after activation by cyclic AMP (cAMP). Newborn screening programs for CF usually consist of an immunoreactive trypsinogen (IRT) assay, followed when IRT is elevated by testing for a panel of CF-causing mutations. Some children, however, may have persistent hypertrypsinogenemia, only one or no identified CFTR gene mutation, and sweat chloride concentrations close to normal values. In vivo demonstration of abnormal CFTR protein function would be an important diagnostic aid in this situation. Measurements of transepithelial nasal potential differences (NPD) in adults accurately characterize CFTR-related ion transport. The aim of the present study is to establish reference values for NPD measurements for healthy children and those with CF aged 3 months to 3 years, the age range of most difficult-to-diagnose patients with suspected CF. The ultimate goal of our study is to validate NPD testing as a diagnostic tool for children with borderline results in neonatal screening. Methods/Design We adapted the standard NPD protocol for young children, designed a special catheter for them, used a slower perfusion rate, and shortened the protocol to include only measurement of basal PD, transepithelial sodium (Na+) transport in response to the Na+ channel inhibitor amiloride, and CFTR-mediated chloride (Cl-) secretion in response to isoproterenol, a β-agonist in a Cl- free solution. The study will include 20 children with CF and 20 healthy control children. CF children will be included only if they carry 2 CF-causing mutations in the CFTR gene or have sweat chloride concentrations > 60 mEq/L or both. The healthy children will be recruited among the siblings of the CF patients, after verification that they do not carry the familial mutation. Discussion A preliminary study of 3 adult control subjects and 4 children older than 12 years with CF verified that the new protocol was well tolerated and produced NPD measurements that did not differ significantly from those obtained with the standard protocol. This preliminary study will provide a basis for interpreting NPD measurements in patients with suspected CF after neonatal screening. Earlier definitive diagnosis should alleviate parental distress and allow earlier therapeutic intervention and genetic counseling.

Published
2006

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