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      Genomewide Association Study of Severe Covid-19 with Respiratory Failure

      research-article
      , Ph.D., , M.Sc., , M.D., Ph.D., , M.D., Ph.D., , M.D., Ph.D., , M.D., Ph.D., , M.D., Ph.D., , M.D., , Ph.D., , Ph.D., , M.D., , Ph.D., , B.S., , Ph.D., , Ph.D., , M.Sc., , Ph.D., , M.Sc., , M.D., Ph.D., , , M.D., Ph.D., , B.S., , M.S., B.S., , B.S., , M.S., Ph.D., , M.D., , M.D., Ph.D., , M.D., , M.D., Ph.D., , M.D., Ph.D., , M.D., , M.S., Ph.D., , M.D., , , B.S., , Ph.D., , M.D., , , Ph.D., , M.D., , M.D., , M.D., Ph.D., , M.D., Ph.D., , B.S., , M.D., Ph.D., , M.Sc., , Ph.D., , M.D., , B.S., , M.D., , M.D., Ph.D., , M.D., Ph.D., , M.D., , Ph.D., , M.D., Ph.D., , Ph.D., , M.D., , M.D., Ph.D., , M.D., Ph.D., , M.D., Ph.D., , M.D., Ph.D., , B.S., M.S., , Ph.D., , M.D., , M.D., , Ph.D., , M.D., , Ph.D., , M.D., , M.Sc., , M.D., , M.Sc., , M.D., Ph.D.,   , Ph.D., , M.D., , Ph.D., , B.S., , M.D., , Ph.D., , Ph.D., , M.D., Ph.D., , M.S.,   , M.D., , M.D., , M.D., , Ph.D., , Ph.D., , M.D., Ph.D., , M.D., Ph.D., , , Ph.D., , M.D., , Ph.D., , M.D., , M.D., , M.D., , M.A., , M.D., Ph.D., , M.Sc., , M.D., , M.D., , M.D., , Ph.D., , M.D., Ph.D., , , Ph.D., , M.D., , M.Sc., , Ph.D., , M.D., , M.D., , M.D., , M.D., , M.S., , M.D., Ph.D., , Ph.D., , M.D., , Ph.D., , M.D., , M.D., , M.D., , M.D., , M.D., Ph.D., , Ph.D., , Ph.D., , M.D., , Ph.D., , M.D., , M.D., , Ph.D., , , Ph.D., , M.D., Ph.D., , Ph.D., , M.D., , , Ph.D., , M.D., Ph.D., , Ph.D., , Ph.D., , Ph.D., , M.D., Ph.D., , M.D., Ph.D., , M.D., , Ph.D., , M.D., Ph.D. *
      The New England Journal of Medicine
      Massachusetts Medical Society
      Keyword part (code): 12Keyword part (keyword): Pulmonary/Critical CareKeyword part (code): 12_1Keyword part (keyword): Pulmonary/Critical Care General , 12, Pulmonary/Critical Care, Keyword part (code): 12_1Keyword part (keyword): Pulmonary/Critical Care General, 12_1, Pulmonary/Critical Care General, Keyword part (code): 13Keyword part (keyword): GeneticsKeyword part (code): 13_1Keyword part (keyword): Genetics General , 13, Genetics, Keyword part (code): 13_1Keyword part (keyword): Genetics General, 13_1, Genetics General, Keyword part (code): 18Keyword part (keyword): Infectious DiseaseKeyword part (code): 18_1Keyword part (keyword): Infectious Disease General , 18, Infectious Disease, Keyword part (code): 18_1Keyword part (keyword): Infectious Disease General, 18_1, Infectious Disease General

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          Abstract

          Background

          There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19.

          Methods

          We conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case–control panels.

          Results

          We detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10 −8) in the meta-analysis of the two case–control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.15×10 −10; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P=4.95×10 −8, respectively). At locus 3p21.31, the association signal spanned the genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1. The association signal at locus 9q34.2 coincided with the ABO blood group locus; in this cohort, a blood-group–specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P=1.48×10 −4) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P=1.06×10 −5).

          Conclusions

          We identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.)

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          Most cited references34

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          Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

          Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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            A Novel Coronavirus from Patients with Pneumonia in China, 2019

            Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
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              Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

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                Author and article information

                Journal
                N Engl J Med
                N. Engl. J. Med
                nejm
                The New England Journal of Medicine
                Massachusetts Medical Society
                0028-4793
                1533-4406
                17 June 2020
                17 June 2020
                : NEJMoa2020283
                Affiliations
                From the Institute of Clinical Molecular Biology, Christian-Albrechts-University (D.E., F.D., J.K., S. May, M. Wendorff, L.W., F.U.-W., X.Y., A.T., A. Peschuck, C.G., G.H.-S., H.E.A., M.C.R., M.E.F.B., M. Schulzky, M. Wittig, N.B., S.J., T.W., W.A., M. D’Amato, A.F.), and University Hospital Schleswig-Holstein, Campus Kiel (N.B., A.F.), Kiel, the Institute for Cardiogenetics, University of Lübeck, Lübeck (J.E.), the German Research Center for Cardiovascular Research, partner site Hamburg–Lübeck–Kiel (J.E.), the University Heart Center Lübeck (J.E.), and the Institute of Transfusion Medicine, University Hospital Schleswig-Holstein (S.G.), Lübeck, Stefan-Morsch-Stiftung, Birkenfeld (M. Schaefer, W.P.), and the Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Plön (O.O., T.L.L.) — all in Germany; Novo Nordisk Foundation Center for Protein Research, Disease Systems Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen (D.E.); the Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute–Donostia University Hospital–University of the Basque Country (L.B., K.G.-E., L.I.-S., P.M.R., J.M.B.), Osakidetza Basque Health Service, Donostialdea Integrated Health Organization, Clinical Biochemistry Department (A.G.C., B.N.J.), and the Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute (M. D’Amato), San Sebastian, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III (L.B., M. Buti, A. Albillos, A. Palom, F.R.-F., B.M., L. Téllez, K.G.-E., L.I.-S., F.M., L.R., M.R.-B., M. Rodríguez-Gandía, P.M.R., M. Romero-Gómez, J.M.B.), the Departments of Gastroenterology (A. Albillos, B.M., L. Téllez, F.M., M. Rodríguez-Gandía), Intensive Care (R.P., A.B.O.), Respiratory Diseases (D.J., A.S., R.N.), Infectious Diseases (C.Q., E.N.), and Anesthesiology (D. Pestaña, N. Martínez), Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, University of Alcalá, and Histocompatibilidad y Biologia Molecular, Centro de Transfusion de Madrid (F.G.S.), Madrid, the Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus (M. Buti, A. Palom, L.R., M.R.-B.), Hospital Clinic, University of Barcelona, and the August Pi i Sunyer Biomedical Research Institute (J.F., F.A., E.S., J.F.-A., L.M., M.H.-T., P.C.), the European Foundation for the Study of Chronic Liver Failure (J.F.), Vall d’Hebron Institut de Recerca (A. Palom, F.R.-F., A.J., S. Marsal), and the Departments of Biochemistry (A.-E.G.-F., F.R.-F., A.C.-G., C.C., A.B.-G.), Intensive Care (R.F.), and Microbiology (T.P.), University Hospital Vall d’Hebron, the Immunohematology Department, Banc de Sang i Teixits, Autonomous University of Barcelona (E.M.-D.), Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, Consortium for Biomedical Research in Epidemiology and Public Health and University of Barcelona, l’Hospitalet (V. Moreno), and Autonoma University of Barcelona (T.P.), Barcelona, Universitat Autònoma de Barcelona, Bellatera (M. Buti, F.R.-F., M.R.-B.), GenomesForLife–GCAT Lab Group, Germans Trias i Pujol Research Institute (A.C.N., I.G.-F., R.C.), and High Content Genomics and Bioinformatics Unit, Germans Trias i Pujol Research Institute (L. Sumoy), Badalona, Institute of Parasitology and Biomedicine Lopez-Neyra, Granada (J.M., M.A.-H.), the Digestive Diseases Unit, Virgen del Rocio University Hospital, Institute of Biomedicine of Seville, University of Seville, Seville (M. Romero-Gómez), and Ikerbasque, Basque Foundation for Science, Bilbao (M. D’Amato, J.M.B.) — all in Spain; the Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca (P.I., C.M.), Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico (D. Prati, G.B., A.Z., A. Bandera, A.G., A.L.F., A. Pesenti, C.P., F.C., F.M.-B., F.P., F.B., G.G., G. Costantino, L. Terranova, L. Santoro, L. Scudeller, M. Carrabba, M. Baldini, M.M., N. Montano, R.G., S.P., S. Aliberti, V. Monzani, S. Bosari, L.V.), the Department of Biomedical Sciences, Humanitas University (R.A., A. Protti, A. Aghemo, A. Lleo, E.M.P., G. Cardamone, M. Cecconi, V.R., S.D.), Humanitas Clinical and Research Center, IRCCS (R.A., A. Protti, A. Aghemo, A. Lleo, A.V., C.A., E.M.P., H.K., I.M., M. Cecconi, M. Ciccarelli, M. Bocciolone, P.P., P.O., P.T., S. Badalamenti, S.D.), University of Milan (A.Z., A. Bandera, A.G., A.L.F., A. Pesenti, F.M.-B., F.P., F.B., G.G., G. Costantino, M.M., N. Montano, R.G., S.P., S. Aliberti, S. Bosari, L.V.), and the Center of Bioinformatics, Biostatistics, and Bioimaging (M.G.V.) and the Phase 1 Research Center (M. Cazzaniga), School of Medicine and Surgery, and the Departments of Emergency, Anesthesia, and Intensive Care (G.F.), Pneumologia (P.F.), and Infectious Diseases (P.B.); University of Milano–Bicocca, Milan, the European Reference Network on Hepatological Diseases (P.I., C.M.) and the Infectious Diseases Unit (P.B.), San Gerardo Hospital, Monza, the Pediatric Departement and Centro Tettamanti–European Reference Network PaedCan, EuroBloodNet, MetabERN–University of Milano–Bicocca–Fondazione MBBM–Ospedale, San Gerardo (A. Biondi, L.R.B., M. D’Angiò), the Gastroenterology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (A. Latiano, O.P.), the Department of Medical Sciences, Università degli Studi di Torino, Turin (S. Aneli, G.M.), and the Italian Bone Marrow Donor Registry, E.O. Ospedali Galliera, Genoa (N.S.) — all in Italy; the Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases, and Transplantation, and the Research Institute for Internal Medicine, Division of Surgery, Inflammatory Diseases, and Transplantation, Oslo University Hospital Rikshospitalet and University of Oslo (M.M.G., J.R.H., T.F., T.H.K.), and the Section for Gastroenterology, Department of Transplantation Medicine, Division for Cancer Medicine, Surgery, and Transplantation, Oslo University Hospital Rikshospitalet (J.R.H., T.F., T.H.K.), Oslo; the School of Biological Sciences, Monash University, Clayton, VIC, Australia (T.Z., M. D’Amato); Private University in the Principality of Liechtenstein (C.G.); the Institute of Biotechnology, Vilnius University, Vilnius, Lithuania (S.J.); and the Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm (M. D’Amato).
                Author notes
                Address reprint requests to Dr. Franke at the Institute of Clinical Molecular Biology and University Hospital of Schleswig-Holstein, Christian-Albrechts-University, Rosalind-Franklin-Str. 12, D-24105 Kiel, Germany, or at a.franke@ 123456mucosa.de ; or to Dr. Karlsen at the Division of Surgery, Inflammatory Diseases, and Transplantation, Oslo University Hospital Rikshospitalet and University of Oslo, Postboks 4950 Nydalen, N-0424 Oslo, Norway, or at t.h.karlsen@ 123456medisin.uio.no .
                [*]

                Dr. Franke serves as an author on behalf of the Covid-19 Host Genetics Initiative; members of the Initiative are listed in Supplementary Appendix 1, available at NEJM.org.

                Dr. Ellinghaus and Ms. Degenhardt and Drs. Valenti, Franke, and Karlsen contributed equally to this article.

                Author information
                http://orcid.org/0000-0002-2281-7498
                http://orcid.org/0000-0001-9561-1338
                http://orcid.org/0000-0001-7423-9864
                http://orcid.org/0000-0001-7240-9567
                http://orcid.org/0000-0002-8160-9613
                http://orcid.org/0000-0001-7742-0028
                http://orcid.org/0000-0001-9293-0691
                http://orcid.org/0000-0002-5900-8096
                http://orcid.org/0000-0001-8909-0345
                http://orcid.org/0000-0002-1735-1400
                Article
                NJ202006173830002
                10.1056/NEJMoa2020283
                7315890
                32558485
                02b3f790-90de-4a71-8188-5a36a4a93758
                Copyright © 2020 Massachusetts Medical Society. All rights reserved.

                This article is made available via the PMC Open Access Subset for unrestricted re-use, except commercial resale, and analyses in any form or by any means with acknowledgment of the original source. These permissions are granted for the duration of the Covid-19 pandemic or until revoked in writing. Upon expiration of these permissions, PMC is granted a license to make this article available via PMC and Europe PMC, subject to existing copyright protections.

                History
                Funding
                Funded by: Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence “Precision Medicine in Chronic Inflammation”., FundRef ;
                Award ID: PMI, EXC2167
                Categories
                Original Article
                Custom metadata
                2020-06-17T17:00:00-04:00
                2020
                06
                17
                17
                00
                00
                -04:00

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