Genomewide Association Study of Severe Covid-19 with Respiratory Failure.,The New England Journal of Medicine

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Genomewide Association Study of Severe Covid-19 with Respiratory Failure.
The New England Journal of Medicine ( IF 158.5 ) Pub Date : 2020-06-17 , DOI: 10.1056/nejmoa2020283
, David Ellinghaus ₁ , Frauke Degenhardt ₁ , Luis Bujanda ₁ , Maria Buti ₁ , Agustín Albillos ₁ , Pietro Invernizzi ₁ , Javier Fernández ₁ , Daniele Prati ₁ , Guido Baselli ₁ , Rosanna Asselta ₁ , Marit M Grimsrud ₁ , Chiara Milani ₁ , Fátima Aziz ₁ , Jan Kässens ₁ , Sandra May ₁ , Mareike Wendorff ₁ , Lars Wienbrandt ₁ , Florian Uellendahl-Werth ₁ , Tenghao Zheng ₁ , Xiaoli Yi ₁ , Raúl de Pablo ₁ , Adolfo G Chercoles ₁ , Adriana Palom ₁ , Alba-Estela Garcia-Fernandez ₁ , Francisco Rodriguez-Frias ₁ , Alberto Zanella ₁ , Alessandra Bandera ₁ , Alessandro Protti ₁ , Alessio Aghemo ₁ , Ana Lleo ₁ , Andrea Biondi ₁ , Andrea Caballero-Garralda ₁ , Andrea Gori ₁ , Anja Tanck ₁ , Anna Carreras Nolla ₁ , Anna Latiano ₁ , Anna Ludovica Fracanzani ₁ , Anna Peschuck ₁ , Antonio Julià ₁ , Antonio Pesenti ₁ , Antonio Voza ₁ , David Jiménez ₁ , Beatriz Mateos ₁ , Beatriz Nafria Jimenez ₁ , Carmen Quereda ₁ , Cinzia Paccapelo ₁ , Christoph Gassner ₁ , Claudio Angelini ₁ , Cristina Cea ₁ , Aurora Solier ₁ , David Pestaña ₁ , Eduardo Muñiz-Diaz ₁ , Elena Sandoval ₁ , Elvezia M Paraboschi ₁ , Enrique Navas ₁ , Félix García Sánchez ₁ , Ferruccio Ceriotti ₁ , Filippo Martinelli-Boneschi ₁ , Flora Peyvandi ₁ , Francesco Blasi ₁ , Luis Téllez ₁ , Albert Blanco-Grau ₁ , Georg Hemmrich-Stanisak ₁ , Giacomo Grasselli ₁ , Giorgio Costantino ₁ , Giulia Cardamone ₁ , Giuseppe Foti ₁ , Serena Aneli ₁ , Hayato Kurihara ₁ , Hesham ElAbd ₁ , Ilaria My ₁ , Iván Galván-Femenia ₁ , Javier Martín ₁ , Jeanette Erdmann ₁ , Jose Ferrusquía-Acosta ₁ , Koldo Garcia-Etxebarria ₁ , Laura Izquierdo-Sanchez ₁ , Laura R Bettini ₁ , Lauro Sumoy ₁ , Leonardo Terranova ₁ , Leticia Moreira ₁ , Luigi Santoro ₁ , Luigia Scudeller ₁ , Francisco Mesonero ₁ , Luisa Roade ₁ , Malte C Rühlemann ₁ , Marco Schaefer ₁ , Maria Carrabba ₁ , Mar Riveiro-Barciela ₁ , Maria E Figuera Basso ₁ , Maria G Valsecchi ₁ , María Hernandez-Tejero ₁ , Marialbert Acosta-Herrera ₁ , Mariella D'Angiò ₁ , Marina Baldini ₁ , Marina Cazzaniga ₁ , Martin Schulzky ₁ , Maurizio Cecconi ₁ , Michael Wittig ₁ , Michele Ciccarelli ₁ , Miguel Rodríguez-Gandía ₁ , Monica Bocciolone ₁ , Monica Miozzo ₁ , Nicola Montano ₁ , Nicole Braun ₁ , Nicoletta Sacchi ₁ , Nilda Martínez ₁ , Onur Özer ₁ , Orazio Palmieri ₁ , Paola Faverio ₁ , Paoletta Preatoni ₁ , Paolo Bonfanti ₁ , Paolo Omodei ₁ , Paolo Tentorio ₁ , Pedro Castro ₁ , Pedro M Rodrigues ₁ , Aaron Blandino Ortiz ₁ , Rafael de Cid ₁ , Ricard Ferrer ₁ , Roberta Gualtierotti ₁ , Rosa Nieto ₁ , Siegfried Goerg ₁ , Salvatore Badalamenti ₁ , Sara Marsal ₁ , Giuseppe Matullo ₁ , Serena Pelusi ₁ , Simonas Juzenas ₁ , Stefano Aliberti ₁ , Valter Monzani ₁ , Victor Moreno ₁ , Tanja Wesse ₁ , Tobias L Lenz ₁ , Tomas Pumarola ₁ , Valeria Rimoldi ₁ , Silvano Bosari ₁ , Wolfgang Albrecht ₁ , Wolfgang Peter ₁ , Manuel Romero-Gómez ₁ , Mauro D'Amato ₁ , Stefano Duga ₁ , Jesus M Banales ₁ , Johannes R Hov ₁ , Trine Folseraas ₁ , Luca Valenti ₁ , Andre Franke ₁ , Tom H Karlsen ₁

Affiliation

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).

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.)

中文翻译：

严重 Covid-19 与呼吸衰竭的全基因组关联研究。

背景

感染严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2)（导致 2019 年冠状病毒病 (Covid-19) 的病毒）的患者的疾病行为存在很大差异。全基因组关联分析可能有助于识别与 Covid-19 发展相关的潜在遗传因素。

方法

我们在欧洲 SARS-CoV-2 大流行的意大利和西班牙震中的 7 家医院开展了一项全基因组关联研究，涉及 1980 名患有 Covid-19 和严重疾病（定义为呼吸衰竭）的患者。经过质量控制并排除人群异常值后，来自意大利的 835 名患者和 1255 名对照参与者以及来自西班牙的 775 名患者和 950 名对照参与者被纳入最终分析。我们总共分析了 8,582,968 个单核苷酸多态性，并对两个病例对照组进行了荟萃分析。

结果

我们检测到基因座 3p21.31 处与 rs11385942 以及基因座 9q34.2 处 rs657152 的交叉复制关联，这在两个病例对照组的荟萃分析中在全基因组水平上显着（P<5×10 ^-8 ）（比值比，1.77；95%置信区间[CI]，1.48至2.11；P=1.15×10 ^-10；比值比，1.32；95% CI，1.20至1.47；P=4.95×10 ^-8）。在基因座 3p21.31，关联信号跨越基因SLC6A20、LZTFL1、CCR9、FYCO1、CXCR6和XCR1。位点 9q34.2 处的关联信号与ABO血型位点一致；在该队列中，血型特异性分析显示，A 型血的风险高于其他血型（比值比，1.45；95% CI，1.20 至 1.75；P=1.48×10 ^-4），并且具有保护作用O 型血与其他血型相比（比值比，0.65；95% CI，0.53 至 0.79；P=1.06×10 ^-5）。