Genomewide Association Study of Severe Covid-19 with Respiratory Failure

被引：1269

作者：

Ellinghaus, David ^{[1
,9
]}

Degenhardt, Frauke ^{[1
]}

Bujanda, Luis ^{[10
,13
]}

Buti, Maria ^{[13
,20
,31
]}

Albillos, Agustin ^{[13
,14
]}

Invernizzi, Pietro ^{[37
,47
]}

Fernandez, Javier ^{[21
,22
]}

Prati, Daniele ^{[38
]}

Baselli, Guido ^{[38
]}

Asselta, Rosanna ^{[39
,40
]}

Grimsrud, Marit M. ^{[54
,55
,56
]}

Milani, Chiara ^{[37
,47
]}

Aziz, Fatima ^{[21
]}

Kassens, Jan ^{[1
]}

May, Sandra ^{[1
]}

Wendorff, Mareike ^{[1
]}

Wienbrandt, Lars ^{[1
]}

Uellendahl-Werth, Florian ^{[1
]}

Zheng, Tenghao ^{[58
]}

Yi, Xiaoli ^{[1
]}

de Pablo, Raul ^{[15
]}

Chercoles, Adolfo G. ^{[11
]}

Palom, Adriana ^{[13
,20
,23
]}

Garcia-Fernandez, Alba-Estela ^{[24
]}

Rodriguez-Frias, Francisco ^{[13
,23
,24
,31
]}

Zanella, Alberto ^{[38
,41
]}

Bandera, Alessandra ^{[38
,41
]}

Protti, Alessandro ^{[39
,40
]}

Aghemo, Alessio ^{[39
,40
]}

Lleo, Ana ^{[39
,40
]}

Biondi, Andrea ^{[49
,50
]}

Caballero-Garralda, Andrea ^{[24
]}

Gori, Andrea ^{[38
,41
]}

Tanck, Anja ^{[1
]}

Nolla, Anna Carreras ^{[32
]}

Latiano, Anna ^{[51
]}

Fracanzani, Anna Ludovica ^{[38
,41
]}

Peschuck, Anna ^{[1
]}

Julia, Antonio ^{[23
]}

Pesenti, Antonio ^{[38
,41
]}

Voza, Antonio ^{[40
]}

Jimenez, David ^{[16
]}

Mateos, Beatriz ^{[13
,14
]}

Jimenez, Beatriz Nafria ^{[11
]}

Quereda, Carmen ^{[17
]}

Paccapelo, Cinzia ^{[38
]}

Gassner, Christoph ^{[1
,59
]}

Angelini, Claudio ^{[40
]}

Cea, Cristina ^{[24
]}

Solier, Aurora ^{[16
]}

机构：

[1] Univ Kiel, Inst Clin Mol Biol, Rosalind Franklin Str 12, D-24105 Kiel, Germany

[2] Univ Hosp Schleswig Holstein, Campus Kiel, Kiel, Germany

[3] Univ Lubeck, Inst Cardiogenet, Lubeck, Germany

[4] German Res Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel, Lubeck, Germany

[5] Univ Heart Ctr Lubeck, Lubeck, Germany

[6] Univ Hosp Schleswig Holstein, Inst Transfus Med, Lubeck, Germany

[7] Stefan Morsch Stiftung, Birkenfeld, Germany

[8] Max Planck Inst Evolutionary Biol, Res Grp Evolutionary Immunogen, Plon, Germany

[9] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Prot Res, Dis Syst Biol, Copenhagen, Denmark

[10] Univ Basque Country, Dept Liver & Gastrointestinal Dis, Biodonostia Hlth Res Inst, Donostia Univ Hospital, San Sebastian, Spain

[11] Donostialdea Integrated Hlth Org, Osakidetza Basque Hlth Serv, Clin Biochem Dept, San Sebastian, Spain

[12] Biodonostia Hlth Res Inst, Dept Liver & Gastrointestinal Dis, San Sebastian, Spain

[13] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain

[14] Univ Alcala, Hosp Univ Ramon y Cajal, Inst Ramon y Cajal Invest Sanitaria, Dept Gastroenterol, Madrid, Spain

[15] Univ Alcala, Hosp Univ Ramon y Cajal, Inst Ramon y Cajal Invest Sanitaria, Dept Intens Care, Madrid, Spain

[16] Univ Alcala, Hosp Univ Ramon y Cajal, Inst Ramon y Cajal Invest Sanitaria, Dept Resp Dis, Madrid, Spain

[17] Univ Alcala, Hosp Univ Ramon y Cajal, Inst Ramon y Cajal Invest Sanitaria, Dept Infect Dis, Madrid, Spain

[18] Univ Alcala, Hosp Univ Ramon y Cajal, Inst Ramon y Cajal Invest Sanitaria, Dept Anesthesiol, Madrid, Spain

[19] Ctr Transfus Madrid, Histocompatibilidad & Biol Mol, Madrid, Spain

[20] Univ Barcelona, Hosp Univ Vall dHebron, Liver Unit, Hosp Clin,Dept Internal Med, Vall dHebron Barcelona Hosp Campus, Barcelona, Spain

[21] August Pi & Sunyer Biomed Res Inst, Barcelona, Spain

[22] European Fdn Study Chron Liver Failure, Barcelona, Spain

[23] Vall dHebron Inst Recerca, Barcelona, Spain

[24] Autonomous Univ Barcelona, Univ Hosp Vall dHebron, Immunohematol Dept, Dept Biochem,Banc Sang & Teixits, Barcelona, Spain

[25] Autonomous Univ Barcelona, Univ Hosp Vall dHebron, Immunohematol Dept, Dept Intens Care,Banc Sang & Teixits, Barcelona, Spain

[26] Autonomous Univ Barcelona, Univ Hosp Vall dHebron, Immunohematol Dept, Dept Microbiol,Banc Sang & Teixits, Barcelona, Spain

[27] Autonomous Univ Barcelona, Univ Hosp Vall dHebron, Immunohematol Dept, Banc Sang & Teixits, Barcelona, Spain

[28] Consortium Biomed Res Epidemiol & Publ Hlth, Catalan Inst Oncol, Bellvitge Biomed Res Inst, Barcelona, Spain

[29] Univ Barcelona, Barcelona, Spain

[30] Autonoma Univ Barcelona, Barcelona, Spain

[31] Univ Autonoma Barcelona, Bellaterra, Spain

[32] Germans Trias & Pujol Res Inst, GenomesForLife GCAT Lab Grp, Badalona, Spain

[33] Germans Trias & Pujol Res Inst, High Content Genom & Bioinformat Unit, Badalona, Spain

[34] Inst Parasitol & Biomed Lopez Neyra, Granada, Spain

[35] Univ Seville, Virgen Rocio Univ Hosp, Inst Biomed Seville, Digest Dis Unit, Seville, Spain

[36] Basque Fdn Sci, Ikerbasque, Bilbao, Spain

[37] Univ Milano Bicocca, Div Gastroenterol, Dept Med & Surg, Ctr Autoimmune Liver Dis, Milan, Italy

[38] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Milan, Italy

[39] Humanitas Univ, Dept Biomed Sci, Milan, Italy

[40] IRCCS, Humanitas Clin & Res Ctr, Milan, Italy

[41] Univ Milan, Milan, Italy

[42] Ctr Bioinformat Biostat & Bioimaging, Milan, Italy

[43] Univ Milano Bicocca, Phase 1 Res Ctr, Sch Med & Surg, Milan, Italy

[44] Univ Milano Bicocca, Dept Emergency Anesthesia & Intens Care, Milan, Italy

[45] Univ Milano Bicocca, Dept Pneumol, Milan, Italy

[46] Univ Milano Bicocca, Dept Infect Dis, Milan, Italy

[47] San Gerardo Hosp, European Reference Network Hepatol Dis, Monza, Italy

[48] San Gerardo Hosp, Infect Dis Unit, Monza, Italy

[49] Univ Milano Bicocca, Fdn MBBM Osped, Pediat Dept, San Gerardo, Italy

[50] Univ Milano Bicocca, Fdn MBBM Osped, European Reference Network PaedCan, EuroBloodNet,MetabERN,Ctr Tettamanti, San Gerardo, Italy

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2020年 / 383卷 / 16期

关键词：

ABO BLOOD-GROUP; WIDE ASSOCIATION; SUSCEPTIBILITY; METAANALYSIS; INFECTION; INCREASES; NUMBER; ACE2;

D O I：

10.1056/NEJMoa2020283

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BackgroundThere 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. MethodsWe 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. ResultsWe 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<5x10(-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=1.15x10(-10); and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P=4.95x10(-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=1.48x10(-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=1.06x10(-5)). ConclusionsWe 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.) During the peak of hospitalizations of patients with severe Covid-19 in Italy and Spain in March, a group of researchers in these and other countries obtained and analyzed samples, resulting in the identification of two chromosomal loci associated with the disorder.

引用

页码：1522 / 1534

页数：13

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