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1. Standards for practical intravenous rapid drug desensitization & delabeling: A WAO committee statement

Author

Emilio Alvarez-Cuesta, Ricardo Madrigal-Burgaleta, Ana D. Broyles, Javier Cuesta-Herranz, Maria Antonieta Guzman-Melendez, Michelle C. Maciag, Elizabeth J. Phillips, Jason A. Trubiano, Johnson T. Wong, Ignacio Ansotegui, F. Runa Ali, Denisse Angel-Pereira, Aleena Banerji, Maria Pilar Berges-Gimeno, Lorena Bernal-Rubio, Knut Brockow, Ricardo Cardona Villa, Mariana C. Castells, Jean-Christoph Caubet, Yoon-Seok Chang, Luis Felipe Ensina, Manana Chikhladze, Anca Mirela Chiriac, Weng-Hung Chung, Motohiro Ebisawa, Bryan Fernandes, Lene Heise Garvey, Maximiliano Gomez, Javier Gomez Vera, Sandra Gonzalez Diaz, David I. Hong, Juan Carlos Ivancevich, Hye-Ryun Kang, David A. Khan, Merin Kuruvilla, Jose Ignacio Larco Sousa, Patricia Latour-Staffeld, Anne Y. Liu, Eric Macy, Hans Jorgen Malling, Jorge Maspero, Sara M. May, Cristobalina Mayorga, Miguel A. Park, Jonathan Peter, Matthieu Picard, Tito Rodriguez-Bouza, Antonino Romano, Mario Sanchez-Borges, Luciana Kase Tanno, Maria Jose Torres, Alicia Ureña-Tavera, Rocco L. Valluzzi, Gerald W. Volcheck, Masao Yamaguchi, Hospital Universitario Ramón y Cajal [Madrid], Universidad de Alcalá - University of Alcalá (UAH), St Bartholomew's Hospital (London), Barts Health NHS Trust [London, UK], Catalan Institute of Oncology (ICO), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), RETIC ARADyAL, University of Chile Clinical Hospital, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], University of Melbourne, Massachusetts General Hospital [Boston], Hospital Quirónsalud Bizkaia [Bilbao], Hospital Universitario De Canarias, Technische Universität München = Technical University of Munich (TUM), Universidad de Antioquia = University of Antioquia [Medellín, Colombia], Hôpitaux Universitaires de Genève (HUG), Seoul National University Bundang Hospital (SNUBH), Seoul National University [Seoul] (SNU), Federal University of Sao Paulo (Unifesp), Akaki Tsereteli State University, Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service d'allergologie et de pneumologie [Hôpital Arnaud de Villeneuve], Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Chang Gung Memorial Hospital [Taipei] (CGMH), Sagamihara National Hospital [Kanagawa, Japan], Copenhagen University Hospital, IT University of Copenhagen (ITU), Catholic University of Salta, Regional Hospital Lic. Adolfo Lopez Mateos (ISSSTE), Hospital Universitario Dr. José Eleuterio González, Brigham & Women’s Hospital [Boston] (BWH), Servicio de Alergia e ImmunologiaBuenos Aires (Clinica Santa Isabel), Seoul National University College of Medicine [Séoul, Corée du Sud] (SNUCM), University of Texas Southwestern Medical Center [Dallas], Emory University School of Medicine, Emory University [Atlanta, GA], Clinica San Felipe, Centro Avanzado de Alergia y Asma de Santo Domingo, Stanford University Medical Center, University of California Medical Center [San Diego], University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Fundación Cidea Allergy and Respiratory Research Unit, University of Nebraska Medical Center, University of Nebraska System, Hospital Regional Universitario de Málaga = Regional University Hospital of Malaga [Spain], Allergy Unit [Malaga, Spain] (National Network ARADyAL), Mayo Clinic [Rochester], University of Cape Town, Hôpital Maisonneuve-Rosemont, Centro de Patología Alérgica, Oasi Maria Santissima Srl [Troina, Italy], Centro Médico Docente La Trinidad, Clínica Unión Medica del Norte, Bambino Gesù Children’s Hospital [Rome, Italy], Chiba University Hospital, CHIRIAC, Anca Mirela, [Madrigal-Burgaleta, Ricardo] Ramon & Cajal Univ Hosp, Madrid, Spain, and [Madrigal-Burgaleta, Ricardo] St Bartholomews Hosp, Resp Dept, Allergy & Severe Asthma Serv, Barts Hlth NHS Trust, 4th Floor,King George 5 Bldg, London EC1A 7BE, England

Subjects
Pulmonary and Respiratory Medicine, Drug desensitization, Immunology, Basophil activation test, Reported penicillin allergy, Monoclonal-antibodies, Penicillins, In-vitro diagnosis, Antibiotic desensitization, Risk-stratification, Biological agents, Skin test, Antibiotics, Carboplatin hypersensitivity, Immunology and Allergy, Chemotherapy, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Beta-lactam allergy, Drug challenge, Risk stratification, Betalactams, Precision medicine, Cross-reactivity, Drug allergy, Delabeling, Personalized medicine, Drug provocation test, Delabel-ing, Ige-mediated hypersensitivity, Immediate allergic reactions, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology
Abstract

International audience; Drug hypersensitivity reactions (DHRs) to intravenous drugs can be severe and might leave patients and doctors in a difficult position where an essential treatment or intervention has to be suspended. Even if virtually any intravenous medication can potentially trigger a life-threatening DHR, chemotherapeutics, biologics, and antibiotics are amongst the intravenous drugs most frequently involved in these reactions. Admittedly, suspending such treatments may negatively impact the survival outcomes or the quality of life of affected patients. Delabeling pathways and rapid drug desensitization (RDD) can help reactive patients stay on first-choice therapies instead of turning to less efficacious, less cost-effective, or more toxic alternatives. However, these are high-complexity and high-risk techniques, which usually need expert teams and allergy-specific techniques (skin testing, in vitro testing, drug provocation testing) to ensure safety, an accurate diagnosis, and personalized management. Unfortunately, there are significant inequalities within and among countries in access to allergy departments with the necessary expertise and resources to offer these techniques and tackle these DHRs optimally. The main objective of this consensus document is to create a great benefit for patients worldwide by aiding allergists to expand the scope of their practice and support them with evidence, data, and experience from leading groups from around the globe. This statement of the Drug Hypersensitivity Committee of the World Allergy Organization (WAO) aims to be a comprehensive practical guide on the technical aspects of implementing acute-onset intravenous hypersensitivity delabeling and RDD for a wide range of drugs. Thus, the manuscript does not only focus on clinical pathways. Instead, it also provides guidance on topics usually left unaddressed, namely, internal validation, continuous quality improvement, creating a healthy multidisciplinary environment, and redesigning care (including a specific supplemental section on a real-life example of how to design a dedicated space that can combine basic and complex diagnostic and therapeutic techniques in allergy).

Published
2022
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2. Beta-lactam-induced immediate hypersensitivity reactions: A genome-wide association study of a deeply phenotyped cohort

Author

Neil H. Shear, Antonino Romano, Anca Mirela Chiriac, Matthew R. Nelson, Peter S. Friedmann, Alla Nakonechna, Rocco Luigi Valluzzi, S. Barrett, Jose A. Cornejo-Garcia, Miguel Blanca, Paola Nicoletti, Munir Pirmohamed, Daniel F. Carr, Pascal Demoly, Aris Floratos, Yufeng Shen, Natalia Blanca-López, Elizabeth J. Phillips, Cristiano Caruso, Laurence McEvoy, Francesco Gaeta, María José Torres, Rebecca Pavlos, Icahn School of Medicine at Mount Sinai [New York] (MSSM), SEMA4, University of Liverpool, University of Southampton, University of Toronto, Sunnybrook Health Sciences Centre, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hospital Universitario Infanta Leonor [Madrid], Instituto de Investigación Biomédica [Malaga, Spain] (IBIMA), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Columbia University [New York], The University of Western Australia (UWA), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Murdoch University, Epidemiology of Allergic and Respiratory Diseases Department [iPlesp] (EPAR), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), 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), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Oasi Maria Santissima Srl [Troina, Italy], Hospital Regional Universitario de Málaga = Regional University Hospital of Malaga [Spain], Herrada, Anthony, Fondazione Policlinico Universitario Agostino Gemelli [Rome], Université de Montpellier (UM), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hospital Regional Universitario de Málaga [Spain]

Subjects
0301 basic medicine, Hypersensitivity, Immediate, Male, Allergy, Linkage disequilibrium, BL, β-Lactam, Genome-wide association study, Cohort Studies, 0302 clinical medicine, QTL, Quantitative trait loci, Immunology and Allergy, Medicine, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, SNP, Single nucleotide polymorphism, Middle Aged, 3. Good health, Anti-Bacterial Agents, Phenotype, Delayed hypersensitivity, penicillins, 030220 oncology & carcinogenesis, Cohort, Female, Anaphylaxis, Drug Allergy, Urticaria, and Angioedema, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, Adult, medicine.medical_specialty, Immunology, Penicillins, Polymorphism, Single Nucleotide, HLA-DQ alpha-Chains, Drug Hypersensitivity, 03 medical and health sciences, Internal medicine, anaphylaxis, Humans, Genetic Predisposition to Disease, Risk factor, pharmacogenomics, business.industry, β-lactams, Odds ratio, medicine.disease, allergy, Cephalosporins, 030104 developmental biology, cephalosporins, business, Type I hypersensitivity, OR, Odds ratio, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract

International audience; Background: β-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (type I) reactions mediated by antigen-specific IgE.Objective: We sought to identify genetic predisposing factors for immediate reactions to β-lactam antibiotics.Methods: Patients with a clinical history of immediate hypersensitivity reactions to either penicillins or cephalosporins, which were immunologically confirmed, were recruited from allergy clinics. A genome-wide association study was conducted on 662 patients (the discovery cohort) with a diagnosis of immediate hypersensitivity and the main finding was replicated in a cohort of 98 Spanish cases, recruited using the same diagnostic criteria as the discovery cohort.Results: Genome-wide association study identified rs71542416 within the Class II HLA region as the top hit (P = 2 × 10-14); this was in linkage disequilibrium with HLA-DRB1∗10:01 (odds ratio, 2.93; P = 5.4 × 10-7) and HLA-DQA1∗01:05 (odds ratio, 2.93, P = 5.4 × 10-7). Haplotype analysis identified that HLA-DRB1∗10:01 was a risk factor even without the HLA-DQA1∗01:05 allele. The association with HLA-DRB1∗10:01 was replicated in another cohort, with the meta-analysis of the discovery and replication cohorts showing that HLA-DRB1∗10:01 increased the risk of immediate hypersensitivity at a genome-wide level (odds ratio, 2.96; P = 4.1 × 10-9). No association with HLA-DRB1∗10:01 was identified in 268 patients with delayed hypersensitivity reactions to β-lactams.Conclusions: HLA-DRB1∗10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required.

Published
2021
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3. Differentiation of COVID-19 signs and symptoms from allergic rhinitis and common cold: An ARIA-EAACI-GA

Author

Jere Reijula, De Yun Wang, Ralph Mösges, Tomohisa Iinuma, Jean Luc Fauquert, Nelson Rosario, Yehia El-Gamal, René Maximiliano Gómez, Tari Haahtela, Vincenzo Patella, Lorenzo Cecchi, Petr Panzner, Yoshitaka Okamoto, Oliver Pfaar, Luis Caraballo, Paulo Augusto Moreira Camargos, Filip Raciborski, Florin Mihaltan, Ken Ohta, Brian J. Lipworth, Kimi Okubo, Juan Carlos Ivancevich, Fulvio Braido, Ioana Agache, Frederico S. Regateiro, Neven Miculinic, Tuula Vasankari, R. Emuzyte, Arunas Valiulis, Yousser Mohammad, Torsten Zuberbier, Osman M. Yusuf, Ewa Jassem, Cezmi A. Akdis, Jean Bousquet, Alessandro Fiocchi, Jan Hagemann, Claus Bachert, Davor Plavec, K. S. Bennoor, Marek Jutel, Désirée Larenas-Linnemann, Stephen Montefort, Stefano Del Giacco, Przemyslaw Kardas, Erkka Valovirta, Mark S. Dykewicz, Antonio Valero, Wienczyslawa Czarlewski, Thomas B. Casale, Gabrielle L. Onorato, Omer Kalayci, Ludger Klimek, Joaquin Sastre, João Fonseca, Siân Williams, Karl Christian Bergmann, Marek Niedoszytko, Bilun Gemicioglu, Mario E. Zernotti, Musa Khaitov, H. Neffen, Robert M. Naclerio, Joaquim Mullol, Ana Pereira, Piotr Kuna, Michael Makris, Maria Teresa Ventura, Ioanna Tsiligianni, Dirceu Solé, Arzu Yorgancioglu, Charlotte Suppli-Ulrik, M. Gotua, Emmanuel P. Prokopakis, Dana Wallace, Jorge Maspero, Wytske Fokkens, Eckard Hamelmann, Antonino Romano, Dejan Dokic, Todor A. Popov, Violeta Kvedariene, Derek K. Chu, Anna Bedbrook, Dermot Ryan, Motohiro Ebisawa, Tomas Chivato, Giovanni Passalacqua, Menachem Rottem, Mário Morais-Almeida, Victoria Cardona, Bolesław Samoliński, Cristiana Stellato, Nikolaos G. Papadopoulos, Milan Sova, Jaime Correia-de-Sousa, Sietze Reitsma, Cemal Cingi, Francesca Puggioni, Robyn E O'Hehir, HUS Inflammation Center, Department of Dermatology, Allergology and Venereology, HUS Internal Medicine and Rehabilitation, Department of Public Health, Clinicum, Keuhkosairauksien yksikkö, Helsinki University Hospital Area, University of Helsinki, University Medical Center of the Johannes Gutenberg-University Mainz, Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), University of Wrocław [Poland] (UWr), Swiss Institute of Allergy and Asthma Research (SIAF), Universität Zürich [Zürich] = University of Zurich (UZH), Transilvania University of Brasov, Humboldt University Of Berlin, Medical Consulting Czarlewski, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), MASK-air, Ghent University Hospital, Sun Yat-Sen University [Guangzhou] (SYSU), Karolinska Institutet [Stockholm], National Institute of Diseases of the Chest and Hospital (NIDCH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Ospedale Policlinico San Martino [Genoa], Universidade Federal de Minas Gerais = Federal University of Minas Gerais [Belo Horizonte, Brazil] (UFMG), University of Cartagena, Foundation for the Development of Medical and Biological Sciences (FUNDEMEB), Vall d'Hebron University Hospital [Barcelona], Allergy Unit [Malaga, Spain] (National Network ARADyAL), Hospital Regional Universitario de Málaga = Regional University Hospital of Malaga [Spain], University of South Florida [Tampa] (USF), Azienda Usl Toscana centro [Firenze], CEU-San Pablo University and HM-Hospitals School of Medicine, McMaster University [Hamilton, Ontario], Eskisehir Osmangazi University, Universidade do Minho = University of Minho [Braga], Life and Health Sciences Research Institute [Braga] (ICVS), University of Minho [Braga], The International Primary Care Respiratory Group (IPCRG), Università degli Studi di Cagliari = University of Cagliari (UniCa), Sts. Cyril and Methodius University, Saint Louis University School of Medicine [St Louis], Sagamihara National Hospital [Kanagawa, Japan], Ain Shams University (ASU), Vilnius University [Vilnius], Service de Pédiatrie Générale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Bambino Gesù Children’s Hospital [Rome, Italy], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA), Center of Research in Health Technologies and Information Systems (CINTESIS), Universidade do Porto = University of Porto, CUF Porto Hospital, Cerrahpasa Faculty of Medicine, Istanbul University, ALAS Medical Institute, Center for Allergy and Immunology Research [Tbilisi], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Universität Bielefeld = Bielefeld University, Chiba University Hospital, Servicio de Alergia e ImmunologiaBuenos Aires (Clinica Santa Isabel), Medical University of Gdańsk, Faculty of Medicine [Hacettepe University], Hacettepe University = Hacettepe Üniversitesi, Medical University of Łódź (MUL), Federal Medicobiological Agency [Moscow, Russian Federation], Hospital Medica Sur [Mexico City, Mexico], Ninewells Hospital and Medical School [Dundee], University General Hospital ' Attikon ' [Athens, Greece], Argentine Association of Allergy and Immunology, Marius Nasta Institute of Pneumology, Tishreen University, Université de Damas = Damascus University, University of Malta [Malta], Hospital CUF Descobertas, Clinical Research International Ltd [Hamburg, Germany] (CRI), Johns Hopkins University School of Medicine [Baltimore], Nemours/Alfred I. du Pont Hospital for Children, Monash University [Melbourne], Tokyo National Hospital, Nippon Medical School [Tokyo, Japon], Medicine Charles University and General Faculty Hospital in Prague, Royal Manchester Children's Hospital, University of Manchester [Manchester], Università degli studi di Genova = University of Genoa (UniGe), 'Santa Maria della Speranza' Hospital, Philipps Universität Marburg = Philipps University of Marburg, J.J. Strossmayer University of Osijek, Children’s Hospital Srebrnjak [Zagreb, Croatia], St. Ivan Rilski University Hospital, University of Crete [Heraklion] (UOC), IRCCS Humanitas [Rozzano, Italy], Medical University of Warsaw - Poland, Centro Hospitalar e Universitário [Coimbra], Amsterdam UMC - Amsterdam University Medical Center, Istituto di Ricovero e Cura a Carattere Scientifico [Troina, Italy] (IRCCS), Oasi Maria Santissima Srl [Troina, Italy], Clinica G.B. Morgagni (Fondazione Mediterranea), Pontifical Catholic University of Paraná (PUCPR), Pontifícia Universidade Católica do Paraná (PUCPR), Ha’Emek Medical Center [Afula, Israel], Pediatric Endocrine Institute [Afula, Israel], Usher Institute of Population Health Sciences and Informatics [Edinburgh, U.K.], University of Edinburgh, Federal University of Sao Paulo (Unifesp), University Hospital Olomouc [Czech Republic], University of Salerno (UNISA), Copenhagen University Hospital, Universitat de Barcelona (UB), European Academy of Paediatrics (EAP/UEMS-SP), University of Turku, Suomen Terveystalo Allergy Clinic, Finnish Lung Health Association, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Nova Southeastern University (NSU), Yong Loo Lin School of Medicine [Singapore], Department of Biology, Faculty of Sciences & Liberal Arts, Celal Bayar University, Manisa Celal Bayar University, The Allergy & Asthma Institute, Pakistan (IPCRG), Universidad Nacional de Villa María, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Allergiezentrum Wiesbaden, Salvy-Córdoba, Nathalie, Ear, Nose and Throat, and AII - Inflammatory diseases

Subjects
0301 basic medicine, Allergy, MESH: Asthma, Common Cold, allergic rhinitis, common cold, cough, COVID-19, smell, Consensus, Humans, SARS-CoV-2, Asthma, Rhinitis, Allergic, Disease, Care, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immunology and Allergy, MESH: COVID-19, Rhinitis, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Common cold, 3. Good health, MESH: Rhinitis, Allergic, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Original Article, medicine.symptom, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Immunology, Signs and symptoms, Asymptomatic, 03 medical and health sciences, Allergic, COVID‐19, Internal medicine, medicine, MESH: SARS-CoV-2, MESH: Consensus, MESH: Humans, business.industry, Rhinitis, Sinusitis, and Upper Airway Disease, CARE, medicine.disease, 030104 developmental biology, 030228 respiratory system, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 3121 General medicine, internal medicine and other clinical medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, ORIGINAL ARTICLES, Airway, business, MESH: Common Cold
Abstract

Background Although there are many asymptomatic patients, one of the problems of COVID-19 is early recognition of the disease. COVID-19 symptoms are polymorphic and may include upper respiratory symptoms. However, COVID-19 symptoms may be mistaken with the common cold or allergic rhinitis. An ARIA-EAACI study group attempted to differentiate upper respiratory symptoms between the three diseases. Methods A modified Delphi process was used. The ARIA members who were seeing COVID-19 patients were asked to fill in a questionnaire on the upper airway symptoms of COVID-19, common cold and allergic rhinitis. Results Among the 192 ARIA members who were invited to respond to the questionnaire, 89 responded and 87 questionnaires were analysed. The consensus was then reported. A two-way ANOVA revealed significant differences in the symptom intensity between the three diseases (p < .001). Conclusions This modified Delphi approach enabled the differentiation of upper respiratory symptoms between COVID-19, the common cold and allergic rhinitis. An electronic algorithm will be devised using the questionnaire.

Published
2021
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4. Practical Guidance for the Evaluation and Management of Drug Hypersensitivity: Specific Drugs

Author

Parul H. Kothari, Johnson T. Wong, Sarita U. Patil, David L. Hepner, Iris M. Otani, Meredith A. Dilley, Craig D. Platt, Margee Louisias, Kimberly G. Blumenthal, Sara Barmettler, Knut Brockow, Alberta L. Wang, Catherine M. Biggs, Dinah Foer, Ana Dioun Broyles, Elizabeth J. Phillips, Stephanie L. Logsdon, Antonino Romano, Ari J. Fried, Timothy Kyin, Matthew P. Giannetti, Kathleen Lee-Sarwar, Michelle C. Maciag, Timothy Lax, Anca Mirela Chiriac, Miriam Verdú, Pascale Dewachter, Samantha Minnicozzi, David I. Hong, Mariana Castells, Josefina Cernadas, Rebecca G. Breslow, Christina S.K. Yee, Kathleen M. Buchheit, Cosby A. Stone, Katherine N. Cahill, Allison E. Norton, Joyce T. Hsu, Jocelyn R. Farmer, Rima Rachid, Aleena Banerji, Andrew J. MacGinnitie, Anna R. Wolfson, Pascal Demoly, Min Jung Lee, Tito Rodriguez, Miguel Park, Matthieu Picard, María José Torres, Joseph X. Zhou, Paige G. Wickner, Patrick J. Brennan, Sarah L. Garon, Elena Crestani, Anne Y. Liu, Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Massachusetts General Hospital [Boston], University of British Columbia (UBC), Brigham & Women’s Hospital [Boston] (BWH), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Hospital de São João [Porto], Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Université de Montpellier (UM), Groupe Hospitalier Universitaire Paris Seine-Saint-Denis (GHUPSSD), University of Virginia [Charlottesville], Beth Israel Deaconess Medical Center [Boston] (BIDMC), Hoag Medical Group [Newport Beach], Stanford University, Cincinnati Children's Hospital Medical Center, Monroe Carell Jr. Children's Hospital at Vanderbilt [Nashville], University of California [San Francisco] (UCSF), University of California, Mayo Clinic [Rochester], Hôpital Maisonneuve-Rosemont, Al-Rashed Allergy Center [Kuwait City], Oasi Maria Santissima Srl [Troina, Italy], Hospital Regional Universitario de Málaga [Spain], Hospital Universitario de Ceuta, and Technical University of Munich (TUM)

Subjects
Drug, MESH: Drug Hypersensitivity, medicine.medical_specialty, media_common.quotation_subject, medicine.medical_treatment, MESH: Pharmaceutical Preparations, Food and drug administration, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, medicine, Immunology and Allergy, MESH: Desensitization, Immunologic, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Intensive care medicine, ComputingMilieux_MISCELLANEOUS, media_common, Desensitization (medicine), Radiocontrast Media, MESH: Humans, business.industry, medicine.disease, 3. Good health, 030228 respiratory system, Intradermal test, Aspirin exacerbated respiratory disease, Penicilloyl polylysine, business, Adverse drug reaction
Abstract

International audience

Published
2020
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5. Extracellular vesicles: pathogenetic, diagnostic and therapeutic value in traumatic brain injury

Author

Stefania Mondello, Andras Buki, Michel Salzet, Eric Peter Thelin, Firas Kobeissy, Carmela Visalli, Gerry Shaw, Dasa Cizkova, Istituto di Ricovero e Cura a Carattere Scientifico [Troina, Italy] (IRCCS), Oasi Maria Santissima Srl [Troina, Italy], University of Messina, Karolinska Institutet [Stockholm], University of Cambridge [UK] (CAM), EnCor Biotechnology Inc . [Gainesville , FL , USA], Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM), Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Slovak Academy of Sciences (SAS), Department of Psychiatry [Gainesville, FL, USA] (McKnight Brain Institute), University of Florida [Gainesville] (UF), American University of Beirut [Beyrouth] (AUB), University of Pecs, Thelin, Eric [0000-0002-2338-4364], Apollo - University of Cambridge Repository, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and SALZET, Michel

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Traumatic brain injury, [SDV]Life Sciences [q-bio], Inflammation, exosomes, Biochemistry, Extracellular vesicles, 03 medical and health sciences, 0302 clinical medicine, Brain Injuries, Traumatic, TBI, medicine, Animals, Humans, Molecular Biology, Cause of death, business.industry, medicine.disease, biomarker, extracellular vesicles, microvesicles, Body Fluids, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Biomarker (medicine), medicine.symptom, business, Biomarkers, 030217 neurology & neurosurgery
Abstract

International audience; Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Accurate classification according to injury-specific and patient-specific characteristics is critical to help informed clinical decision-making and to the pursuit of precision medicine in TBI. Reliable biomarker signatures for improved TBI diagnostics are required but still an unmet need. Areas covered: Extracellular vesicles (EVs) represent a new class of biomarker candidates in TBI. These nano-sized vesicles have key roles in cell signaling profoundly impacting pathogenic pathways, progression and long-term sequelae of TBI. As such EVs might provide novel neurobiological insights, enhance our understanding of the molecular mechanisms underlying TBI pathophysiology and recovery, and serve as biomarker signatures and therapeutic targets and delivery systems. Expert commentary: EVs are fast gaining momentum in TBI research, paving the way for new transformative diagnostic and treatment approaches. Their potential to sort out TBI variability and active involvement in the mechanisms underpinning different clinical phenotypes point out unique opportunities for improved classification, risk-stratification ad intervention, harboring promise of predictive, personalized, and even preemptive therapeutic strategies. Although a great deal of progress has been made, substantial efforts are still required to ensure the needed rigorous validation and reproducibility for clinical implementation of EVs.

Published
2018
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6. Sleep deprivation and Modafinil affect cortical sources of resting state electroencephalographic rhythms in healthy young adults

Author

Jill C. Richardson, Pierre Payoux, Nicolas Chauveau, Claire Thalamas, Juergen Dukart, Maria Teresa Pascarelli, Raffaele Ferri, Philippe Derambure, Déborah Méligne, J.L. Bourriez, Claudio Del Percio, Roberta Lizio, Olivier Blin, Giuseppe Noce, Claudio Babiloni, Catherine Cassé-Perrot, David Bartrés-Faz, Laura Lanteaume, Dominique Deplanque, Régis Bordet, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), CHU Lille, Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), IRCCS SDN Napoli, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM), Imagerie cérébrale et handicaps neurologiques (ICHN), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique - Innovation Technologique de Lille - CIC 1403 - CIC 9301 (CIC Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), F. Hoffmann-La Roche [Basel], Istituto di Ricovero e Cura a Carattere Scientifico [Troina, Italy] (IRCCS), Oasi Maria Santissima Srl [Troina, Italy], GlaxoSmithKline [Stevenage, UK] (GSK), GlaxoSmithKline [Headquarters, London, UK] (GSK), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], and Otten, Lisa

Subjects
wakefulness-promoting agents, Alzheimer’s disease (AD), Modafinil, Audiology, Resting state electroencephalographic (rsEEG) rhythms, 0302 clinical medicine, Alzheimer's disease (AD), exact low-resolution brain electromagnetic source tomography (eLORETA), resting state electroencephalographic (rsEEG) rhythms, sleep deprivation, adult, alpha rhythm, beta rhythm, brain waves, cerebral cortex, cross-over studies, delta rhythm, electroencephalography, functional laterality, camma rhythm, healthy volunteers, humans, male, rest, sample size, theta rhythm, wakefulness, Gamma Rhythm, media_common, medicine.diagnostic_test, 05 social sciences, Neuropsychological test, Sensory Systems, Sleep deprivation, Neurology, medicine.symptom, medicine.drug, Vigilance (psychology), medicine.medical_specialty, media_common.quotation_subject, 050105 experimental psychology, Arousal, 03 medical and health sciences, Physiology (medical), medicine, Exact low-resolution brain electromagnetic source tomography (eLORETA), 0501 psychology and cognitive sciences, Resting state fMRI, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Alertness, Delta Rhythm, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Objective It has been reported that sleep deprivation affects the neurophysiological mechanisms underpinning the vigilance. Here, we tested the following hypotheses in the PharmaCog project ( www.pharmacog.org ): (i) sleep deprivation may alter posterior cortical delta and alpha sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms in healthy young adults; (ii) after the sleep deprivation, a vigilance enhancer may recover those rsEEG source markers. Methods rsEEG data were recorded in 36 healthy young adults before (Pre-sleep deprivation) and after (Post-sleep deprivation) one night of sleep deprivation. In the Post-sleep deprivation, these data were collected after a single dose of PLACEBO or MODAFINIL. rsEEG cortical sources were estimated by eLORETA freeware. Results In the PLACEBO condition, the sleep deprivation induced an increase and a decrease in posterior delta (2–4 Hz) and alpha (8–13 Hz) source activities, respectively. In the MODAFINIL condition, the vigilance enhancer partially recovered those source activities. Conclusions The present results suggest that posterior delta and alpha source activities may be both related to the regulation of human brain arousal and vigilance in quiet wakefulness. Significance Future research in healthy young adults may use this methodology to preselect new symptomatic drug candidates designed to normalize brain arousal and vigilance in seniors with dementia.

Published
2019
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7. Folate and fetal programming: a play in epigenomics?

Author

Jean-Luc Daval, Jean-Louis Guéant, Rosa-Maria Guéant-Rodriguez, Farès Namour, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Istituto di Ricovero e Cura a Carattere Scientifico [Troina, Italy] (IRCCS), and Oasi Maria Santissima Srl [Troina, Italy]

Subjects
medicine.medical_specialty, Offspring, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Population, Biology, folate, Models, Biological, Epigenesis, Genetic, Fetal Development, PGC1-α, 03 medical and health sciences, Folic Acid, SIRT1, 0302 clinical medicine, Endocrinology, Sirtuin 1, Internal medicine, medicine, Humans, Epigenetics, Heterochromatin assembly, education, 030304 developmental biology, Epigenomics, 2. Zero hunger, Genetics, 0303 health sciences, education.field_of_study, epigenetics, Methylation, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, 3. Good health, fetal programming, epigenomics, DNA methylation, Female, Genomic imprinting, 030217 neurology & neurosurgery, Transcription Factors
Abstract

International audience; Folate plays a key role in the interactions between nutrition, fetal programming, and epigenomics. Maternal folate status influences DNA methylation, inheritance of the agouti phenotype, expression of imprinting genes, and the effects of mycotoxin FB1 on heterochromatin assembly in rodent offspring. Deficiency in folate and other methyl donors increases birth defects and produces visceral manifestations of fetal programming, including liver and heart steatosis, through imbalanced methylation and acetylation of PGC1-α and decreased SIRT1 expression, and produces persistent cognitive and learning disabilities through impaired plasticity and hippocampal atrophy. Maternal folate supplementation also produces long-term epigenomic effects in offspring, some beneficial and others negative. Deciphering these mechanisms will help understanding the discordances between experimental models and population studies of folate deficiency and supplementation.

Published
2013
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8. Approach to the diagnosis of drug hypersensitivity reactions: similarities and differences between Europe and North America

Author

Patrizia Bonadonna, Kimberly G. Blumenthal, María José Torres, Eric Macy, Annick Barbaud, Pascal Demoly, David A. Khan, Miguel A. Park, Antonino Romano, Gülfem Çelik, Mariana Castells, Werner Aberer, Cristobalina Mayorga, Allergy Unit [Malaga, Spain] (National Network ARADyAL), Hospital Regional Universitario de Málaga [Spain], The Andalusian Center for Nanomedicine and Biotechnology (BIONAND), Allergy Unit [Italy], Presidio Columbus [Italy]-Allergologia - Columbus - Policlinico Gemelli [Italy], Istituto di Ricovero e Cura a Carattere Scientifico [Troina, Italy] (IRCCS), Oasi Maria Santissima Srl [Troina, Italy], Department of Chest Diseases [Ankara, Turkey], Division of Immunology and Allergy [Ankara, Turkey], Ankara University School of Medicine [Turkey]-Ankara University School of Medicine [Turkey], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Internal Medicine [Dallas, TX, USA], University of Texas Southwestern Medical Center [Dallas], Kaiser Permanente, Division of Allergic Diseases [Rochester, MN, USA], Mayo Clinic [Rochester], Division of Rheumatology, Allergy and Immunology [Boston, MA, USA] (Department of Medicine), Massachusetts General Hospital [Boston], Department of Dermatology [Graz, Austria], Medical University Graz, Division of Rheumatology, Immunology and Allergy [Boston, MSA, USA], Brigham and Women's Hospital [Boston], Service de dermatologie et allergologie [CHU Tenon], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Sorbonne Paris Cité (USPC), Allergy Unit [Verona, Italy], Azienda ospedaliera universitaria integrata di Verona [Italy], [Torres,MJ, Mayorga,] Allergy Unit, National Network ARADyAL, IBIMA-Regional University Hospital of Malaga-UMA, Malaga, Spain. [Torres,MJ] BIONAND-Andalusian Centre for Nanomedicine and Biotechnology, Malaga, Spain. [Romano,A] Allergy Unit, Presidio Columbus, Rome, Italy. IRCCS Oasi Maria S.S., Troina, Italy. [Celik,G] Department of Chest Diseases, Division of Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey. [Demoly,P] Hôpital Arnaud de Villeneuve, University Hospital of Montpellier and Sorbonne Universités, UPMC Paris , IPLESP, Equipe EPAR, Paris, France. [Khan,DA] Department of Internal Medicine, Division of Allergy and Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA. [Macy,E] Kaiser Permanente Health Care Program, San Diego, CA, USA. [Park,M] Mayo Clinic College of Medicine, Division of Allergic Diseases, Mayo Clinic, Rochester, MN , USA. [Blumenthal,K] Division of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. [Aberer,W] Department of Dermatology, Medical University of Graz, Graz, Austria. [Castells,M] Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Boston, MSA, USA. [Barbaud,A] Sorbonne Universities, UPMC Univ Paris, Dermatology and Allergology Department, Tenon Hospital (AP-HP), Paris, France. [Allergy Unit, IBIMA-Regional University Hospital of Malaga-UMA (Pavilion C) Malaga, Spain. [Bonadonna,P] Allergy Unit, Azienda Ospedaliera Universitaria Intergrata of Verona, Verona, Italy., BMC, BMC, Hospital Regional Universitario de Málaga = Regional University Hospital of Malaga [Spain], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Allergy, [SDV]Life Sciences [q-bio], Provocation test, Presumptive diagnosis, Review, Anafilaxia, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Health Care::Population Characteristics::Demography::Ethnic Groups [Medical Subject Headings], Clinical history, Salud pública, Diagnosis, Immunology and Allergy, media_common, education.field_of_study, Geographical Locations::Geographic Locations::Americas::North America::United States [Medical Subject Headings], Estados Unidos, Health Care::Population Characteristics::Health::Public Health [Medical Subject Headings], 3. Good health, Humanos, [SDV] Life Sciences [q-bio], Europe, Diseases::Chemically-Induced Disorders::Drug-Related Side Effects and Adverse Reactions::Drug Hypersensitivity [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Evaluation Studies as Topic::Drug Evaluation [Medical Subject Headings], Pruebas cutáneas, IgE, Drug, Hipersensibilidad a las drogas, Europa, Evaluación de Medicamentos, Pulmonary and Respiratory Medicine, medicine.medical_specialty, In vitro test, media_common.quotation_subject, Concordance, Immunology, Population, Sensitization, 03 medical and health sciences, Skin test, medicine, Hypersensitivity, Intensive care medicine, education, business.industry, Public health, T-cells, Diseases::Immune System Diseases::Hypersensitivity::Hypersensitivity, Immediate::Anaphylaxis [Medical Subject Headings], medicine.disease, United States, Surgery, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Immunologic Tests::Skin Tests [Medical Subject Headings], Grupos étnicos, 030104 developmental biology, 030228 respiratory system, Drug provocation test, Geographical Locations::Geographic Locations::Europe [Medical Subject Headings], business, Unit States
Abstract

International audience; AbstractDrug hypersensitivity reactions (DHRs) affect an unknown proportion of the general population, and are an important public health problem due to their potential to cause life-threatening anaphylaxis and rare severe cutaneous allergic reactions. DHR evaluations are frequently needed in both ambulatory and hospital settings and have a complex diagnosis that requires a detailed clinical history and other tests that may include in vitro tests and in vivo procedures such as skin tests and drug provocation tests. Although over the years both European and U.S. experts have published statements on general procedures for evaluating DHRs, a substantial discordance in their daily management exists. In this review, we highlight both the differences and the similarities between the European and U.S. perspectives. While a general consensus exists on the importance of skin tests for evaluating DHRs, concordance between Americans and Europeans exists solely regarding their use in immediate reactions and the fact that a confirmation of a presumptive diagnosis by drug provocation tests is often the only reliable way to establish a diagnosis. Finally, great heterogeneity exists in the application of in vitro tests, which require further study to be well validated.

Published
2016
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9. Allergy to betalactams and nucleotide-binding oligomerization domain (NOD) gene polymorphisms

Author

A. Barbaud, JA Cornejo, Jean-Louis Guéant, M. Blanca, Francesco Gaeta, Abderrahim Oussalah, I Gastin, Antonino Romano, AC Bursztejn, Rosa-Maria Guéant-Rodriguez, Céline Chéry, Service de Dermatologie et Allergologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Complesso Integrato Columbus, Istituto di Ricovero e Cura a Carattere Scientifico [Troina, Italy] (IRCCS), Oasi Maria Santissima Srl [Troina, Italy], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Allergy Service [Carlos Haya Hospital], and Hospital Regional Universitario Carlos Haya

Subjects
Adult, Male, Allergy, [SDV]Life Sciences [q-bio], Immunology, Nod2 Signaling Adaptor Protein, Nod, Biology, Immunoglobulin E, beta-Lactams, betalactam allergy, polymorphism, Atopy, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Genetic, NOD2, Nod1 Signaling Adaptor Protein, Genotype, medicine, Hypersensitivity, Immunology and Allergy, Humans, Allele, 030304 developmental biology, Genetics, Inflammation, 0303 health sciences, Polymorphism, Genetic, Settore MED/09 - MEDICINA INTERNA, Case-control study, Allergens, Middle Aged, medicine.disease, NOD gene, digestive system diseases, 030228 respiratory system, Case-Control Studies, biology.protein, Female, IgE
Abstract

Background Polymorphisms of interleukin genes related to IgE production and inflammation are predictors of hypersensitivity to betalactam, but nothing is known on the influence of NOD genes, despite their association with inflammation and atopy. Objective To evaluate the association of NOD2 and NOD1 polymorphisms with betalactam allergy. Method We genotyped 3 polymorphisms of NOD2 and 1 of NOD1 in 368 Italian and 387 Spanish patients, compared with 368 and 326 controls, respectively. Results CT/TT genotypes of rs2066845 of NOD2 predicted a lower risk in Italy (P = 0.003), while WT/insC genotype of rs5743293 (also in leucine-rich repeat domain) predicted a higher risk in Spain (P = 0.007). G allele of rs2066845 was associated with a higher level of IgE in the Italian population. Conclusion The mirrored influence of these NOD2 polymorphisms on betalactam allergy in two populations suggests a link with pathways of inflammation and/or atopy through mechanisms, which need to be clarified.

Published
2013
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10. Author Correction: Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Author

Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, Boland A, Vronskaya M, van der Lee SJ, Amlie-Wolf A, Bellenguez C, Frizatti A, Chouraki V, Martin ER, Sleegers K, Badarinarayan N, Jakobsdottir J, Hamilton-Nelson KL, Moreno-Grau S, Olaso R, Raybould R, Chen Y, Kuzma AB, Hiltunen M, Morgan T, Ahmad S, Vardarajan BN, Epelbaum J, Hoffmann P, Boada M, Beecham GW, Garnier JG, Harold D, Fitzpatrick AL, Valladares O, Moutet ML, Gerrish A, Smith AV, Qu L, Bacq D, Denning N, Jian X, Zhao Y, Del Zompo M, Fox NC, Choi SH, Mateo I, Hughes JT, Adams HH, Malamon J, Sanchez-Garcia F, Patel Y, Brody JA, Dombroski BA, Naranjo MCD, Daniilidou M, Eiriksdottir G, Mukherjee S, Wallon D, Uphill J, Aspelund T, Cantwell LB, Garzia F, Galimberti D, Hofer E, Butkiewicz M, Fin B, Scarpini E, Sarnowski C, Bush WS, Meslage S, Kornhuber J, White CC, Song Y, Barber RC, Engelborghs S, Sordon S, Voijnovic D, Adams PM, Vandenberghe R, Mayhaus M, Cupples LA, Albert MS, De Deyn PP, Gu W, Himali JJ, Beekly D, Squassina A, Hartmann AM, Orellana A, Blacker D, Rodriguez-Rodriguez E, Lovestone S, Garcia ME, Doody RS, Munoz-Fernadez C, Sussams R, Lin H, Fairchild TJ, Benito YA, Holmes C, Karamujić-Čomić H, Frosch MP, Thonberg H, Maier W, Roshchupkin G, Ghetti B, Giedraitis V, Kawalia A, Li S, Huebinger RM, Kilander L, Moebus S, Hernández I, Kamboh MI, Brundin R, Turton J, Yang Q, Katz MJ, Concari L, Lord J, Beiser AS, Keene CD, Helisalmi S, Kloszewska I, Kukull WA, Koivisto AM, Lynch A, Tarraga L, Larson EB, Haapasalo A, Lawlor B, Mosley TH, Lipton RB, Solfrizzi V, Gill M, Longstreth WT Jr, Montine TJ, Frisardi V, Diez-Fairen M, Rivadeneira F, Petersen RC, Deramecourt V, Alvarez I, Salani F, Ciaramella A, Boerwinkle E, Reiman EM, Fievet N, Rotter JI, Reisch JS, Hanon O, Cupidi C, Uitterlinden AGA, Royall DR, Dufouil C, Maletta RG, de Rojas I, Sano M, Brice A, Cecchetti R, George-Hyslop PS, Ritchie K, Tsolaki M, Tsuang DW, Dubois B, Craig D, Wu CK, Soininen H, Avramidou D, Albin RL, Fratiglioni L, Germanou A, Apostolova LG, Keller L, Koutroumani M, Arnold SE, Panza F, Gkatzima O, Asthana S, Hannequin D, Whitehead P, Atwood CS, Caffarra P, Hampel H, Quintela I, Carracedo Á, Lannfelt L, Rubinsztein DC, Barnes LL, Pasquier F, Frölich L, Barral S, McGuinness B, Beach TG, Johnston JA, Becker JT, Passmore P, Bigio EH, Schott JM, Bird TD, Warren JD, Boeve BF, Lupton MK, Bowen JD, Proitsi P, Boxer A, Powell JF, Burke JR, Kauwe JSK, Burns JM, Mancuso M, Buxbaum JD, Bonuccelli U, Cairns NJ, McQuillin A, Cao C, Livingston G, Carlson CS, Bass NJ, Carlsson CM, Hardy J, Carney RM, Bras J, Carrasquillo MM, Guerreiro R, Allen M, Chui HC, Fisher E, Masullo C, Crocco EA, DeCarli C, Bisceglio G, Dick M, Ma L, Duara R, Graff-Radford NR, Evans DA, Hodges A, Faber KM, Scherer M, Fallon KB, Riemenschneider M, Fardo DW, Heun R, Farlow MR, Kölsch H, Ferris S, Leber M, Foroud TM, Heuser I, Galasko DR, Giegling I, Gearing M, Hüll M, Geschwind DH, Gilbert JR, Morris J, Green RC, Mayo K, Growdon JH, Feulner T, Hamilton RL, Harrell LE, Drichel D, Honig LS, Cushion TD, Huentelman MJ, Hollingworth P, Hulette CM, Hyman BT, Marshall R, Jarvik GP, Meggy A, Abner E, Menzies GE, Jin LW, Leonenko G, Real LM, Jun GR, Baldwin CT, Grozeva D, Karydas A, Russo G, Kaye JA, Kim R, Jessen F, Kowall NW, Vellas B, Kramer JH, Vardy E, LaFerla FM, Jöckel KH, Lah JJ, Dichgans M, Leverenz JB, Mann D, Levey AI, Pickering-Brown S, Lieberman AP, Klopp N, Lunetta KL, Wichmann HE, Lyketsos CG, Morgan K, Marson DC, Brown K, Martiniuk F, Medway C, Mash DC, Nöthen MM, Masliah E, Hooper NM, McCormick WC, Daniele A, McCurry SM, Bayer A, McDavid AN, Gallacher J, McKee AC, van den Bussche H, Mesulam M, Brayne C, Miller BL, Riedel-Heller S, Miller CA, Miller JW, Al-Chalabi A, Morris JC, Shaw CE, Myers AJ, Wiltfang J, O'Bryant S, Olichney JM, Alvarez V, Parisi JE, Singleton AB, Paulson HL, Collinge J, Perry WR, Mead S, Peskind E, Cribbs DH, Rossor M, Pierce A, Ryan NS, Poon WW, Nacmias B, Potter H, Sorbi S, Quinn JF, Sacchinelli E, Raj A, Spalletta G, Raskind M, Caltagirone C, Bossù P, Orfei MD, Reisberg B, Clarke R, Reitz C, Smith AD, Ringman JM, Warden D, Roberson ED, Wilcock G, Rogaeva E, Bruni AC, Rosen HJ, Gallo M, Rosenberg RN, Ben-Shlomo Y, Sager MA, Mecocci P, Saykin AJ, Pastor P, Cuccaro ML, Vance JM, Schneider JA, Schneider LS, Slifer S, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Swerdlow RH, Tang M, Tanzi RE, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Van Eldik LJ, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Wilhelmsen KC, Williamson J, Wingo TS, Woltjer RL, Wright CB, Yu CE, Yu L, Saba Y, Pilotto A, Bullido MJ, Peters O, Crane PK, Bennett D, Bosco P, Coto E, Boccardi V, De Jager PL, Lleo A, Warner N, Lopez OL, Ingelsson M, Deloukas P, Cruchaga C, Graff C, Gwilliam R, Fornage M, Goate AM, Sanchez-Juan P, Kehoe PG, Amin N, Ertekin-Taner N, Berr C, Debette S, Love S, Launer LJ, Younkin SG, Dartigues JF, Corcoran C, Ikram MA, Dickson DW, Nicolas G, Campion D, Tschanz J, Schmidt H, Hakonarson H, Clarimon J, Munger R, Schmidt R, Farrer LA, Van Broeckhoven C, O'Donovan MC, DeStefano AL, Jones L, Haines JL, Deleuze JF, Owen MJ, Gudnason V, Mayeux R, Escott-Price V, Psaty BM, Ramirez A, Wang LS, Ruiz A, van Duijn CM, Holmans PA, Seshadri S, Williams J, Amouyel P, Schellenberg GD, Lambert JC, and Pericak-Vance MA

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019
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11. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Author

Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, Boland A, Vronskaya M, van der Lee SJ, Amlie-Wolf A, Bellenguez C, Frizatti A, Chouraki V, Martin ER, Sleegers K, Badarinarayan N, Jakobsdottir J, Hamilton-Nelson KL, Moreno-Grau S, Olaso R, Raybould R, Chen Y, Kuzma AB, Hiltunen M, Morgan T, Ahmad S, Vardarajan BN, Epelbaum J, Hoffmann P, Boada M, Beecham GW, Garnier JG, Harold D, Fitzpatrick AL, Valladares O, Moutet ML, Gerrish A, Smith AV, Qu L, Bacq D, Denning N, Jian X, Zhao Y, Del Zompo M, Fox NC, Choi SH, Mateo I, Hughes JT, Adams HH, Malamon J, Sanchez-Garcia F, Patel Y, Brody JA, Dombroski BA, Naranjo MCD, Daniilidou M, Eiriksdottir G, Mukherjee S, Wallon D, Uphill J, Aspelund T, Cantwell LB, Garzia F, Galimberti D, Hofer E, Butkiewicz M, Fin B, Scarpini E, Sarnowski C, Bush WS, Meslage S, Kornhuber J, White CC, Song Y, Barber RC, Engelborghs S, Sordon S, Voijnovic D, Adams PM, Vandenberghe R, Mayhaus M, Cupples LA, Albert MS, De Deyn PP, Gu W, Himali JJ, Beekly D, Squassina A, Hartmann AM, Orellana A, Blacker D, Rodriguez-Rodriguez E, Lovestone S, Garcia ME, Doody RS, Munoz-Fernadez C, Sussams R, Lin H, Fairchild TJ, Benito YA, Holmes C, Karamujić-Čomić H, Frosch MP, Thonberg H, Maier W, Roshchupkin G, Ghetti B, Giedraitis V, Kawalia A, Li S, Huebinger RM, Kilander L, Moebus S, Hernández I, Kamboh MI, Brundin R, Turton J, Yang Q, Katz MJ, Concari L, Lord J, Beiser AS, Keene CD, Helisalmi S, Kloszewska I, Kukull WA, Koivisto AM, Lynch A, Tarraga L, Larson EB, Haapasalo A, Lawlor B, Mosley TH, Lipton RB, Solfrizzi V, Gill M, Longstreth WT Jr, Montine TJ, Frisardi V, Diez-Fairen M, Rivadeneira F, Petersen RC, Deramecourt V, Alvarez I, Salani F, Ciaramella A, Boerwinkle E, Reiman EM, Fievet N, Rotter JI, Reisch JS, Hanon O, Cupidi C, Andre Uitterlinden AG, Royall DR, Dufouil C, Maletta RG, de Rojas I, Sano M, Brice A, Cecchetti R, George-Hyslop PS, Ritchie K, Tsolaki M, Tsuang DW, Dubois B, Craig D, Wu CK, Soininen H, Avramidou D, Albin RL, Fratiglioni L, Germanou A, Apostolova LG, Keller L, Koutroumani M, Arnold SE, Panza F, Gkatzima O, Asthana S, Hannequin D, Whitehead P, Atwood CS, Caffarra P, Hampel H, Quintela I, Carracedo Á, Lannfelt L, Rubinsztein DC, Barnes LL, Pasquier F, Frölich L, Barral S, McGuinness B, Beach TG, Johnston JA, Becker JT, Passmore P, Bigio EH, Schott JM, Bird TD, Warren JD, Boeve BF, Lupton MK, Bowen JD, Proitsi P, Boxer A, Powell JF, Burke JR, Kauwe JSK, Burns JM, Mancuso M, Buxbaum JD, Bonuccelli U, Cairns NJ, McQuillin A, Cao C, Livingston G, Carlson CS, Bass NJ, Carlsson CM, Hardy J, Carney RM, Bras J, Carrasquillo MM, Guerreiro R, Allen M, Chui HC, Fisher E, Masullo C, Crocco EA, DeCarli C, Bisceglio G, Dick M, Ma L, Duara R, Graff-Radford NR, Evans DA, Hodges A, Faber KM, Scherer M, Fallon KB, Riemenschneider M, Fardo DW, Heun R, Farlow MR, Kölsch H, Ferris S, Leber M, Foroud TM, Heuser I, Galasko DR, Giegling I, Gearing M, Hüll M, Geschwind DH, Gilbert JR, Morris J, Green RC, Mayo K, Growdon JH, Feulner T, Hamilton RL, Harrell LE, Drichel D, Honig LS, Cushion TD, Huentelman MJ, Hollingworth P, Hulette CM, Hyman BT, Marshall R, Jarvik GP, Meggy A, Abner E, Menzies GE, Jin LW, Leonenko G, Real LM, Jun GR, Baldwin CT, Grozeva D, Karydas A, Russo G, Kaye JA, Kim R, Jessen F, Kowall NW, Vellas B, Kramer JH, Vardy E, LaFerla FM, Jöckel KH, Lah JJ, Dichgans M, Leverenz JB, Mann D, Levey AI, Pickering-Brown S, Lieberman AP, Klopp N, Lunetta KL, Wichmann HE, Lyketsos CG, Morgan K, Marson DC, Brown K, Martiniuk F, Medway C, Mash DC, Nöthen MM, Masliah E, Hooper NM, McCormick WC, Daniele A, McCurry SM, Bayer A, McDavid AN, Gallacher J, McKee AC, van den Bussche H, Mesulam M, Brayne C, Miller BL, Riedel-Heller S, Miller CA, Miller JW, Al-Chalabi A, Morris JC, Shaw CE, Myers AJ, Wiltfang J, O'Bryant S, Olichney JM, Alvarez V, Parisi JE, Singleton AB, Paulson HL, Collinge J, Perry WR, Mead S, Peskind E, Cribbs DH, Rossor M, Pierce A, Ryan NS, Poon WW, Nacmias B, Potter H, Sorbi S, Quinn JF, Sacchinelli E, Raj A, Spalletta G, Raskind M, Caltagirone C, Bossù P, Orfei MD, Reisberg B, Clarke R, Reitz C, Smith AD, Ringman JM, Warden D, Roberson ED, Wilcock G, Rogaeva E, Bruni AC, Rosen HJ, Gallo M, Rosenberg RN, Ben-Shlomo Y, Sager MA, Mecocci P, Saykin AJ, Pastor P, Cuccaro ML, Vance JM, Schneider JA, Schneider LS, Slifer S, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Swerdlow RH, Tang M, Tanzi RE, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Van Eldik LJ, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Wilhelmsen KC, Williamson J, Wingo TS, Woltjer RL, Wright CB, Yu CE, Yu L, Saba Y, Pilotto A, Bullido MJ, Peters O, Crane PK, Bennett D, Bosco P, Coto E, Boccardi V, De Jager PL, Lleo A, Warner N, Lopez OL, Ingelsson M, Deloukas P, Cruchaga C, Graff C, Gwilliam R, Fornage M, Goate AM, Sanchez-Juan P, Kehoe PG, Amin N, Ertekin-Taner N, Berr C, Debette S, Love S, Launer LJ, Younkin SG, Dartigues JF, Corcoran C, Ikram MA, Dickson DW, Nicolas G, Campion D, Tschanz J, Schmidt H, Hakonarson H, Clarimon J, Munger R, Schmidt R, Farrer LA, Van Broeckhoven C, C O'Donovan M, DeStefano AL, Jones L, Haines JL, Deleuze JF, Owen MJ, Gudnason V, Mayeux R, Escott-Price V, Psaty BM, Ramirez A, Wang LS, Ruiz A, van Duijn CM, Holmans PA, Seshadri S, Williams J, Amouyel P, Schellenberg GD, Lambert JC, and Pericak-Vance MA

Subjects
Aged, Case-Control Studies, Female, Genetic Testing methods, Genome-Wide Association Study methods, Haplotypes genetics, Humans, Lipid Metabolism genetics, Male, Alzheimer Disease genetics, Amyloid beta-Peptides genetics, Genetic Loci genetics, Genetic Predisposition to Disease genetics, Immunity genetics, Lipids genetics, tau Proteins genetics
Abstract

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10 -7 ), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

Published
2019
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12. Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease.

Author

Dalmasso MC, Brusco LI, Olivar N, Muchnik C, Hanses C, Milz E, Becker J, Heilmann-Heimbach S, Hoffmann P, Prestia FA, Galeano P, Avalos MSS, Martinez LE, Carulla ME, Azurmendi PJ, Liberczuk C, Fezza C, Sampaño M, Fierens M, Jemar G, Solis P, Medel N, Lisso J, Sevillano Z, Bosco P, Bossù P, Spalletta G, Galimberti D, Mancuso M, Nacmias B, Sorbi S, Mecocci P, Pilotto A, Caffarra P, Panza F, Bullido M, Clarimon J, Sánchez-Juan P, Coto E, Sanchez-Garcia F, Graff C, Ingelsson M, Bellenguez C, Castaño EM, Kairiyama C, Politis DG, Kochen S, Scaro H, Maier W, Jessen F, Mangone CA, Lambert JC, Morelli L, and Ramirez A

Subjects
Aged, Aged, 80 and over, Argentina ethnology, Black People genetics, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Indians, North American genetics, Male, Middle Aged, White People genetics, Adaptor Proteins, Signal Transducing genetics, Alzheimer Disease ethnology, Alzheimer Disease genetics, Membrane Glycoproteins genetics, Phospholipase C gamma genetics, Receptors, Immunologic genetics
Abstract

Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer's disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.

Published
2019
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13. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

Author

Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, Kunkle BW, Boland A, Raybould R, Bis JC, Martin ER, Grenier-Boley B, Heilmann-Heimbach S, Chouraki V, Kuzma AB, Sleegers K, Vronskaya M, Ruiz A, Graham RR, Olaso R, Hoffmann P, Grove ML, Vardarajan BN, Hiltunen M, Nöthen MM, White CC, Hamilton-Nelson KL, Epelbaum J, Maier W, Choi SH, Beecham GW, Dulary C, Herms S, Smith AV, Funk CC, Derbois C, Forstner AJ, Ahmad S, Li H, Bacq D, Harold D, Satizabal CL, Valladares O, Squassina A, Thomas R, Brody JA, Qu L, Sánchez-Juan P, Morgan T, Wolters FJ, Zhao Y, Garcia FS, Denning N, Fornage M, Malamon J, Naranjo MCD, Majounie E, Mosley TH, Dombroski B, Wallon D, Lupton MK, Dupuis J, Whitehead P, Fratiglioni L, Medway C, Jian X, Mukherjee S, Keller L, Brown K, Lin H, Cantwell LB, Panza F, McGuinness B, Moreno-Grau S, Burgess JD, Solfrizzi V, Proitsi P, Adams HH, Allen M, Seripa D, Pastor P, Cupples LA, Price ND, Hannequin D, Frank-García A, Levy D, Chakrabarty P, Caffarra P, Giegling I, Beiser AS, Giedraitis V, Hampel H, Garcia ME, Wang X, Lannfelt L, Mecocci P, Eiriksdottir G, Crane PK, Pasquier F, Boccardi V, Henández I, Barber RC, Scherer M, Tarraga L, Adams PM, Leber M, Chen Y, Albert MS, Riedel-Heller S, Emilsson V, Beekly D, Braae A, Schmidt R, Blacker D, Masullo C, Schmidt H, Doody RS, Spalletta G, Longstreth WT Jr, Fairchild TJ, Bossù P, Lopez OL, Frosch MP, Sacchinelli E, Ghetti B, Yang Q, Huebinger RM, Jessen F, Li S, Kamboh MI, Morris J, Sotolongo-Grau O, Katz MJ, Corcoran C, Dunstan M, Braddel A, Thomas C, Meggy A, Marshall R, Gerrish A, Chapman J, Aguilar M, Taylor S, Hill M, Fairén MD, Hodges A, Vellas B, Soininen H, Kloszewska I, Daniilidou M, Uphill J, Patel Y, Hughes JT, Lord J, Turton J, Hartmann AM, Cecchetti R, Fenoglio C, Serpente M, Arcaro M, Caltagirone C, Orfei MD, Ciaramella A, Pichler S, Mayhaus M, Gu W, Lleó A, Fortea J, Blesa R, Barber IS, Brookes K, Cupidi C, Maletta RG, Carrell D, Sorbi S, Moebus S, Urbano M, Pilotto A, Kornhuber J, Bosco P, Todd S, Craig D, Johnston J, Gill M, Lawlor B, Lynch A, Fox NC, Hardy J, Albin RL, Apostolova LG, Arnold SE, Asthana S, Atwood CS, Baldwin CT, Barnes LL, Barral S, Beach TG, Becker JT, Bigio EH, Bird TD, Boeve BF, Bowen JD, Boxer A, Burke JR, Burns JM, Buxbaum JD, Cairns NJ, Cao C, Carlson CS, Carlsson CM, Carney RM, Carrasquillo MM, Carroll SL, Diaz CC, Chui HC, Clark DG, Cribbs DH, Crocco EA, DeCarli C, Dick M, Duara R, Evans DA, Faber KM, Fallon KB, Fardo DW, Farlow MR, Ferris S, Foroud TM, Galasko DR, Gearing M, Geschwind DH, Gilbert JR, Graff-Radford NR, Green RC, Growdon JH, Hamilton RL, Harrell LE, Honig LS, Huentelman MJ, Hulette CM, Hyman BT, Jarvik GP, Abner E, Jin LW, Jun G, Karydas A, Kaye JA, Kim R, Kowall NW, Kramer JH, LaFerla FM, Lah JJ, Leverenz JB, Levey AI, Li G, Lieberman AP, Lunetta KL, Lyketsos CG, Marson DC, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Morris JC, Murrell JR, Myers AJ, O'Bryant S, Olichney JM, Pankratz VS, Parisi JE, Paulson HL, Perry W, Peskind E, Pierce A, Poon WW, Potter H, Quinn JF, Raj A, Raskind M, Reisberg B, Reitz C, Ringman JM, Roberson ED, Rogaeva E, Rosen HJ, Rosenberg RN, Sager MA, Saykin AJ, Schneider JA, Schneider LS, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Swerdlow RH, Tanzi RE, Thornton-Wells TA, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Van Eldik LJ, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Wilhelmsen KC, Williamson J, Wingo TS, Woltjer RL, Wright CB, Yu CE, Yu L, Garzia F, Golamaully F, Septier G, Engelborghs S, Vandenberghe R, De Deyn PP, Fernadez CM, Benito YA, Thonberg H, Forsell C, Lilius L, Kinhult-Stählbom A, Kilander L, Brundin R, Concari L, Helisalmi S, Koivisto AM, Haapasalo A, Dermecourt V, Fievet N, Hanon O, Dufouil C, Brice A, Ritchie K, Dubois B, Himali JJ, Keene CD, Tschanz J, Fitzpatrick AL, Kukull WA, Norton M, Aspelund T, Larson EB, Munger R, Rotter JI, Lipton RB, Bullido MJ, Hofman A, Montine TJ, Coto E, Boerwinkle E, Petersen RC, Alvarez V, Rivadeneira F, Reiman EM, Gallo M, O'Donnell CJ, Reisch JS, Bruni AC, Royall DR, Dichgans M, Sano M, Galimberti D, St George-Hyslop P, Scarpini E, Tsuang DW, Mancuso M, Bonuccelli U, Winslow AR, Daniele A, Wu CK, Peters O, Nacmias B, Riemenschneider M, Heun R, Brayne C, Rubinsztein DC, Bras J, Guerreiro R, Al-Chalabi A, Shaw CE, Collinge J, Mann D, Tsolaki M, Clarimón J, Sussams R, Lovestone S, O'Donovan MC, Owen MJ, Behrens TW, Mead S, Goate AM, Uitterlinden AG, Holmes C, Cruchaga C, Ingelsson M, Bennett DA, Powell J, Golde TE, Graff C, De Jager PL, Morgan K, Ertekin-Taner N, Combarros O, Psaty BM, Passmore P, Younkin SG, Berr C, Gudnason V, Rujescu D, Dickson DW, Dartigues JF, DeStefano AL, Ortega-Cubero S, Hakonarson H, Campion D, Boada M, Kauwe JK, Farrer LA, Van Broeckhoven C, Ikram MA, Jones L, Haines JL, Tzourio C, Launer LJ, Escott-Price V, Mayeux R, Deleuze JF, Amin N, Holmans PA, Pericak-Vance MA, Amouyel P, van Duijn CM, Ramirez A, Wang LS, Lambert JC, Seshadri S, Williams J, and Schellenberg GD

Subjects
Amino Acid Sequence, Case-Control Studies, Exome genetics, Gene Expression Profiling, Gene Frequency, Genetic Predisposition to Disease genetics, Genotype, Humans, Linkage Disequilibrium, Odds Ratio, Protein Interaction Maps genetics, Sequence Homology, Amino Acid, Adaptor Proteins, Signal Transducing genetics, Alzheimer Disease genetics, Immunity, Innate genetics, Membrane Glycoproteins genetics, Microglia metabolism, Phospholipase C gamma genetics, Polymorphism, Single Nucleotide, Receptors, Immunologic genetics
Abstract

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10 -4 ) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10 -8 ) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10 -10 , odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 -10 , OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 -14 , OR = 1.67, MAF cases = 0.0143, MAF controls = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Published
2017
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