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2 results on '"University Hospitals Leuven and Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium"'

1. Genome-wide whole blood transcriptome profiling in a large European cohort of systemic sclerosis patients

Author

Zuzanna Makowska, Ricard Cervera, Lorenzo Beretta, László Kovács, Marta E. Alarcón-Riquelme, Guillermo Barturen, Isabel Almeida, Divi Cornec, Javier Martín, Jacques-Olivier Pers, Ellen De Langhe, Nicolas Hunzelmann, Carlo Chizzolini, Maria Gerosa, Martin Kerick, Ralf Lesche, Chiara Bellocchi, Barbara Vigone, Rafaela Ortega Castro, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Centre for Genomics and Oncological Research Pfizer [Granada, Spain], Universidad de Granada = University of Granada (UGR)-Andalusian Regional Government [Granada, Spain], Università degli Studi di Milano = University of Milan (UNIMI), Universitätsklinikum Köln (Uniklinik Köln), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University Hospitals Leuven [Leuven], Department of Clinical Sciences and Community Health [Milan, Italy], Hospital Clinic, IDIBAPS, Universidad de Barcelona, Ciberes, Barcelona, Spain., Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC), Universidad de Córdoba = University of Córdoba [Córdoba]-Hospital Universitario Reina Sofía, University of Szeged [Szeged], CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Hôpital Universitaire de Genève, Geneva, Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Bayer Pharma AG [Berlin], Instituto de Parasitología y Biomedicina 'López-Neyra', PRECISESADS SSc substudy group, PRECISESADS Flow Cytometry study group : Doreen Belz, Eduardo Collantes-Estevez, Francesca Ingegnoli, Yolanda Jimenez Gómez, Chary Lopez Pedrera, Rik Lories, Gaia Montanelli, Silvia Piantoni, Ignasi Rodriguez Pinto, Carlos Vasconcelos, Christophe Jamin, Concepción Marañón, Lucas Le Lann, Quentin Simon, Bénédicte Rouvière, Nieves Varela, Brian Muchmore, Aleksandra Dufour, Montserrat Alvarez, Jonathan Cremer, Nuria Barbarroja, Velia Gerl, Laleh Khodadadi, Qingyu Cheng, Anne Buttgereit, Aurélie De Groof, Julie Ducreux, Elena Trombetta, Tianlu Li, Damiana Alvarez-Errico, Torsten Witte, Katja Kniesch, Nancy Azevedo, Esmeralda Neves, Sambasiva Rao, Pierre-Emmanuel Jouve., Michel, Geneviève, University of Granada [Granada]-Andalusian Regional Government [Granada, Spain], University of Milan, University Hospitals Leuven and Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium, Università degli Studi di Milano [Milano] (UNIMI), Universidad de Córdoba [Cordoba]-Hospital Universitario Reina Sofía, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Universitaire de Genève, and European Commission

Subjects
MESH: Interferon Type I, MESH: Signal Transduction, Male, 0301 basic medicine, Microarray, systemic sclerosis, Autoimmunity, Diseases, Pathogenesis, DISEASE, MESH: Scleroderma, Systemic, Cohort Studies, Transcriptome, 0302 clinical medicine, Immunophenotyping, Platelet degranulation, Gene expression, MESH: Sequence Analysis, RNA, Immunology and Allergy, Medicine, RNA-Seq, MESH: Cohort Studies, GENE-EXPRESSION, MESH: Aged, MESH: Middle Aged, Toll-Like Receptors, Middle Aged, 3. Good health, Europe, Interferon Type I, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, epidemiology, Life Sciences & Biomedicine, MESH: Toll-Like Receptors, Signal Transduction, Adult, MESH: Immunophenotyping, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Context (language use), Systemic Sclerosis, Computational biology, General Biochemistry, Genetics and Molecular Biology, MESH: Gene Expression Profiling, 03 medical and health sciences, Rheumatology, MESH: Autoimmunity, Humans, autoimmune diseases, Gene, Aged, 030203 arthritis & rheumatology, Science & Technology, MESH: Humans, Scleroderma, Systemic, Sequence Analysis, RNA, business.industry, MESH: Transcriptome, Gene Expression Profiling, RNA, MESH: Adult, Microarray Analysis, Expressió gènica, MESH: Male, MESH: Microarray Analysis, Scleroderma (Disease), 030104 developmental biology, MESH: Genome-Wide Association Study, MESH: Europe, Esclerodèrmia, business, MESH: Female, Genome-Wide Association Study
Abstract

Objectives: The analysis of annotated transcripts from genome-wide expression studies may help to understand the pathogenesis of complex diseases, such as systemic sclerosis (SSc). We performed a whole blood (WB) transcriptome analysis on RNA collected in the context of the European PRECISESADS project, aiming at characterising the pathways that differentiate SSc from controls and that are reproducible in geographically diverse populations. Methods: Samples from 162 patients and 252 controls were collected in RNA stabilisers. Cases and controls were divided into a discovery (n=79+163; Southern Europe) and validation cohort (n=83+89; Central-Western Europe). RNA sequencing was performed by an Illumina assay. Functional annotations of Reactome pathways were performed with the Functional Analysis of Individual Microarray Expression (FAIME) algorithm. In parallel, immunophenotyping of 28 circulating cell populations was performed. We tested the presence of differentially expressed genes/pathways and the correlation between absolute cell counts and RNA transcripts/FAIME scores in regression models. Results significant in both populations were considered as replicated. Results: Overall, 15 224 genes and 1277 functional pathways were available; of these, 99 and 225 were significant in both sets. Among replicated pathways, we found a deregulation in type-I interferon, Toll-like receptor cascade, tumour suppressor p53 protein function, platelet degranulation and activation. RNA transcripts or FAIME scores were jointly correlated with cell subtypes with strong geographical differences; neutrophils were the major determinant of gene expression in SSc-WB samples. Conclusions: We discovered a set of differentially expressed genes/pathways validated in two independent sets of patients with SSc, highlighting a number of deregulated processes that have relevance for the pathogenesis of autoimmunity and SSc., This work was supported by eU/eFPia/innovative Medicines initiative Joint Undertaking PrecisesaDs Grant no. 115 565.

Published
2020

2. A new molecular classification to drive precision treatment strategies in primary Sjögren's syndrome

Author

Soret, Perrine, Le Dantec, Christelle, Desvaux, Emiko, Foulquier, Nathan, Chassagnol, Bastien, Hubert, Sandra, Jamin, Christophe, Barturen, Guillermo, Desachy, Guillaume, Devauchelle-Pensec, Valérie, Boudjeniba, Cheïma, Cornec, Divi, Saraux, Alain, Jousse-Joulin, Sandrine, Barbarroja, Nuria, Rodríguez-Pintó, Ignasi, De Langhe, Ellen, Beretta, Lorenzo, Chizzolini, Carlo, Kovács, László, Witte, Torsten, Bettacchioli, Eléonore, Buttgereit, Anne, Makowska, Zuzanna, Lesche, Ralf, Borghi, Maria Orietta, Martin, Javier, Courtade-Gaiani, Sophie, Xuereb, Laura, Guedj, Mickaël, Moingeon, Philippe, Alarcón-Riquelme, Marta, Laigle, Laurence, Pers, Jacques-Olivier, Vigone, Barbara, Lauwerys, Bernard, Maudoux, Anne-Lise, Vasconcelos, Carlos, Tavares, Ana, Faria, Raquel, Brandão, Mariana, Campar, Ana, Marinho, António, Farinha, Fátima, Almeida, Isabel, Gonzalez-Gay Mantecón, Miguel Angel, Blanco Alonso, Ricardo, Corrales Martínez, Alfonso, Cervera, Ricard, Espinosa, Gerard, Lories, Rik, Hunzelmann, Nicolas, Belz, Doreen, Baerlecken, Niklas, Stummvoll, Georg, Zauner, Michael, Lehner, Michaela, Collantes, Eduardo, Ortega-Castro, Rafaela, Aguirre-Zamorano, Ma Angeles, Escudero-Contreras, Alejandro, Castro-Villegas, Ma Carmen, Jiménez Gómez, Yolanda, Ortego, Norberto, Fernández Roldán, María Concepción, Raya, Enrique, Jiménez Moleón, Inmaculada, de Ramon, Enrique, Díaz Quintero, Isabel, Meroni, Pier Luigi, Gerosa, Maria, Schioppo, Tommaso, Artusi, Carolina, Zuber, Aleksandra, Wynar, Donatienne, Balog, Attila, Deák, Magdolna, Bocskai, Márta, Dulic, Sonja, Kádár, Gabriella, Hiepe, Falk, Thiel, Silvia, Rodriguez Maresca, Manuel, López-Berrio, Antonio, Aguilar-Quesada, Rocío, Navarro-Linares, Héctor, Ioannou, Yiannis, Chamberlain, Chris, Marovac, Jacqueline, Alarcón Riquelme, Marta, Gomes Anjos, Tania, Marañón, Concepción, Le Lann, Lucas, Simon, Quentin, Rouvière, Bénédicte, Varela, Nieves, Muchmore, Brian, Dufour, Aleksandra, Alvarez, Montserrat, Cremer, Jonathan, Lopez-Pedrera, Chary, Gerl, Velia, Khodadadi, Laleh, Cheng, Qingyu, De Groof, Aurélie, Ducreux, Julie, Trombetta, Elena, Li, Tianlu, Alvarez-Errico, Damiana, Kniesch, Katja, Azevedo, Nancy, Neves, Esmeralda, Rao, Sambasiva, Jouve, Pierre-Emmanuel, Agence Nationale de la Recherche (France), European Commission, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Cluj-Napoca Unit-The Net-Work of International Francophone Clinical Epidemiology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca Unit-The Net-Work of International Francophone Clinical Epidemiology, Iuliu Hatieganu University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania., Iuliu Hatieganu University of Medicine & Pharmacy, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), University of South Florida [Tampa] (USF), Cluj-Napoca Unit-The Net-Work of International Francophone Clinical Epidemiology, Iuliu Hatieganu University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania., Institut de Recherches Internationales Servier [Suresnes] (IRIS), Centre for Genomics and Oncological Reearch (GENYO), CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC), Universidad de Córdoba [Cordoba]-Hospital Universitario Reina Sofía, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University Hospitals Leuven and Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium, Maggiore Hospital, IRCCS Foundation, Milano, Department of Pathology and Immunology [Geneva, Switzerland], University of Geneva [Switzerland], University of Szeged [Szeged], Clinic for Immunology and Rhematology, Hannover Medical School, Hanover, Germany, Hôpital Morvan - CHRU de Brest (CHU - BREST ), Pharmaceuticals Division Bayer Pharma Aktiengesellschaft, Università degli Studi di Milano [Milano] (UNIMI), Instituto de Parasitología y Biomedicina 'López-Neyra' (IPBLN), Consejo Superior de Investigaciones Científicas (CSIC), Centre for Genomics and Oncological Research (GENYO) Pfizer, University of Granada, and Università degli Studi di Milano and IRCCS Maggiore Policlinico Hospital, Mangiagalli and Regina Elena Foundation

Subjects
Male, Oncology, MESH: Inflammation, MESH: Flow Cytometry, Disease, DISEASE, 0302 clinical medicine, Molecular classification, Databases, Genetic, MESH: Interferons, Databases, Protein, MESH: Cytokines, MESH: Middle Aged, Molecular medicine, Malalties autoimmunitàries, MESH: Polymorphism, Single Nucleotide, ASSOCIATION, Flow Cytometry, Pathophysiology, 3. Good health, Multigene Family, Marcadors bioquímics, Cohort, Cytokines, Science & Technology - Other Topics, Epigenetics, cell cycle, MESH: Computational Biology, medicine.medical_specialty, Science, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, splicing, MESH: Cross-Sectional Studies, Rheumatology, MESH: Computer Simulation, Humans, Computer Simulation, RITUXIMAB, SIGNATURES, Autoantibodies, Science & Technology, MESH: Humans, MESH: Transcriptome, Computational Biology, MESH: Adult, DNA Methylation, Immune dysregulation, Epigenètica, Clinical trial, CLINICAL PHENOTYPES, Cross-Sectional Studies, 030104 developmental biology, MESH: Sjogren's Syndrome, MESH: Genome-Wide Association Study, chronic lymphocytic leukemia, MESH: Multigene Family, MESH: Female, Biomarkers, RESPONSES, 0301 basic medicine, Proteome, Autoimmune diseases, General Physics and Astronomy, medicine.disease_cause, Cohort Studies, Clinical trials, MESH: DNA Methylation, MESH: Autoantibodies, RNA-Seq, liquid chromatography-tandem mass spectrometry, MESH: Cohort Studies, MESH: Databases, Genetic, Multidisciplinary, Biochemical markers, Middle Aged, MESH: Chemokines, Multidisciplinary Sciences, MESH: Proteome, Sjogren's Syndrome, Assaigs clinics, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Chemokines, HYDROXYCHLOROQUINE, Adult, INTERFERON, MESH: Databases, Protein, MEDLINE, Polymorphism, Single Nucleotide, MECHANISMS, Internal medicine, cell cycle, chronic lymphocytic leukemia, liquid chromatography-tandem mass spectrometry, splicing, medicine, MESH: RNA-Seq, Inflammation, 030203 arthritis & rheumatology, business.industry, General Chemistry, EFFICACY, MESH: Male, MESH: Biomarkers, Interferons, Transcriptome, business, Assaigs clínics, Genome-Wide Association Study
Abstract

There is currently no approved treatment for primary Sjögren’s syndrome, a disease that primarily affects adult women. The difficulty in developing effective therapies is -in part- because of the heterogeneity in the clinical manifestation and pathophysiology of the disease. Finding common molecular signatures among patient subgroups could improve our understanding of disease etiology, and facilitate the development of targeted therapeutics. Here, we report, in a cross-sectional cohort, a molecular classification scheme for Sjögren’s syndrome patients based on the multi-omic profiling of whole blood samples from a European cohort of over 300 patients, and a similar number of age and gender-matched healthy volunteers. Using transcriptomic, genomic, epigenetic, cytokine expression and flow cytometry data, combined with clinical parameters, we identify four groups of patients with distinct patterns of immune dysregulation. The biomarkers we identify can be used by machine learning classifiers to sort future patients into subgroups, allowing the re-evaluation of response to treatments in clinical trials., Sjögren’s syndrome, a disease that primarily affects women, is poorly understood. Here, the authors combine data from a large cohort of patients and healthy controls to identify biomarkers that distinguish patient subgroups to improve our understanding of the disease and facilitate drug development.

Published
2021

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