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重症COVID-19合并呼吸衰竭的全基因组关联研究
Genomewide Association Study of Severe Covid-19 with Respiratory Failure


The Severe Covid-19 GWAS Group* 其他 • 2020.10.15
相关阅读
• 重症COVID-19 • 瑞德西韦同情用药治疗重症COVID-19患者 • 洛匹那韦-利托那韦治疗重症COVID-19成人住院患者的试验

通过GWAS在宿主基因组学水平探寻新冠病毒易感性与患病严重性

 

何西淼

华中科技大学同济医学院基础医学院生理学系/基因组与蛋白质组研究中心

 

新冠病毒(SARS-CoV-2)感染者绝大多数只有轻微症状,甚至无症状,但也有一部分人病情非常严重,出现了呼吸衰竭需要吸氧或者呼吸机治疗。临床医生和研究人员已经发现男性、老年人和有心血管疾病/糖尿病等基础疾病的人群更容易出现呼吸衰竭,但仍有年轻而且没有基础疾病的患者发展成重症,甚至死亡。这些观察都提示,COVID-19的发病过程,致病机制和严重性可能会因人而异。6月17日在线发表于《新英格兰医学杂志》(NEJM)的一项最新研究1通过全基因组关联研究(GWAS)探讨了个人遗传背景如何影响新冠病毒感染者的患病严重性。

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摘要


背景

COVID-19致病病毒SARS-CoV-2感染患者的临床病情大相径庭。全基因组关联分析有可能发现涉及COVID-19发病的潜在遗传因素。

 

方法

我们在1,980例重症COVID-19(定义为呼吸衰竭)患者中开展了全基因组关联研究,这些患者来自欧洲SARS-CoV-2疫情最严重的意大利和西班牙的7家医院。经过质量控制并排除人群离群值后,纳入最终分析的患者包括意大利的835例患者和1,255名对照,以及西班牙的775例患者和950名对照。我们总计分析了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

在两个病例-对照组的荟萃分析中,我们检测到与基因座3p21.31处的rs11385942以及与基因座9q34.2处的rs657152的交叉复制关联,其在全基因组水平上具有显著意义(P<5×10-8)(比值比,1.77;95%置信区间[CI],1.48~2.11;P=1.15×10-10;比值比,1.32;95% CI,1.20~1.47;P=4.95×10-8)。在基因座3p21.31,关联信号跨越了SLC6A20、LZTFL1、CCR9、FYCO1、CXCR6XCR1基因。基因座9q34.2的关联信号与ABO血型基因座重合;在该患者队列中,针对血型进行的分析显示,A型血患者的患病风险高于其他血型患者(比值比,1.45;95% CI,1.20~1.75;P=1.48×10-4);而O型血与其他血型相比具有保护作用(比值比,0.65;95% CI,0.53~0.79;P=1.06×10-5)。

 

结论

我们发现3p21.31基因簇是COVID-19合并呼吸衰竭患者的遗传易感基因座,并证实ABO血型系统有可能与COVID-19相关(由Stein Erik Hagen等资助)。





作者信息

The Severe Covid-19 GWAS Group*
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). 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@mucosa.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@medisin.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.

 

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