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Genomewide Association Study of Severe Covid-19 with Respiratory Failure.

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.).

SUBMITTER: Severe Covid-19 GWAS Group

PROVIDER: S-EPMC7315890 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Genomewide Association Study of Severe Covid-19 with Respiratory Failure.

Ellinghaus David D Degenhardt Frauke F Bujanda Luis L Buti Maria M Albillos Agustín A Invernizzi Pietro P Fernández Javier J Prati Daniele D Baselli Guido G Asselta Rosanna R Grimsrud Marit M MM Milani Chiara C Aziz Fátima F Kässens Jan J May Sandra S Wendorff Mareike M Wienbrandt Lars L Uellendahl-Werth Florian F Zheng Tenghao T Yi Xiaoli X de Pablo Raúl R Chercoles Adolfo G AG Palom Adriana A Garcia-Fernandez Alba-Estela AE Rodriguez-Frias Francisco F Zanella Alberto A Bandera Alessandra A Protti Alessandro A Aghemo Alessio A Lleo Ana A Biondi Andrea A Caballero-Garralda Andrea A Gori Andrea A Tanck Anja A Carreras Nolla Anna A Latiano Anna A Fracanzani Anna Ludovica AL Peschuck Anna A Julià Antonio A Pesenti Antonio A Voza Antonio A Jiménez David D Mateos Beatriz B Nafria Jimenez Beatriz B Quereda Carmen C Paccapelo Cinzia C Gassner Christoph C Angelini Claudio C Cea Cristina C Solier Aurora A Pestaña David D Muñiz-Diaz Eduardo E Sandoval Elena E Paraboschi Elvezia M EM Navas Enrique E García Sánchez Félix F Ceriotti Ferruccio F Martinelli-Boneschi Filippo F Peyvandi Flora F Blasi Francesco F Téllez Luis L Blanco-Grau Albert A Hemmrich-Stanisak Georg G Grasselli Giacomo G Costantino Giorgio G Cardamone Giulia G Foti Giuseppe G Aneli Serena S Kurihara Hayato H ElAbd Hesham H My Ilaria I Galván-Femenia Iván I Martín Javier J Erdmann Jeanette J Erdmann Jeanette J Ferrusquía-Acosta Jose J Garcia-Etxebarria Koldo K Izquierdo-Sanchez Laura L Bettini Laura R LR Sumoy Lauro L Terranova Leonardo L Moreira Leticia L Santoro Luigi L Scudeller Luigia L Mesonero Francisco F Roade Luisa L Rühlemann Malte C MC Schaefer Marco M Carrabba Maria M Riveiro-Barciela Mar M Figuera Basso Maria E ME Valsecchi Maria G MG Hernandez-Tejero María M Acosta-Herrera Marialbert M D'Angiò Mariella M Baldini Marina M Cazzaniga Marina M Schulzky Martin M Cecconi Maurizio M Wittig Michael M Ciccarelli Michele M Rodríguez-Gandía Miguel M Bocciolone Monica M Miozzo Monica M Montano Nicola N Braun Nicole N Sacchi Nicoletta N Martínez Nilda N Özer Onur O Palmieri Orazio O Faverio Paola P Preatoni Paoletta P Bonfanti Paolo P Omodei Paolo P Tentorio Paolo P Castro Pedro P Rodrigues Pedro M PM Blandino Ortiz Aaron A de Cid Rafael R Ferrer Ricard R Gualtierotti Roberta R Nieto Rosa R Goerg Siegfried S Badalamenti Salvatore S Marsal Sara S Matullo Giuseppe G Pelusi Serena S Juzenas Simonas S Aliberti Stefano S Monzani Valter V Moreno Victor V Wesse Tanja T Lenz Tobias L TL Pumarola Tomas T Rimoldi Valeria V Bosari Silvano S Albrecht Wolfgang W Peter Wolfgang W Romero-Gómez Manuel M D'Amato Mauro M D'Amato Mauro M Duga Stefano S Banales Jesus M JM Hov Johannes R JR Folseraas Trine T Valenti Luca L Franke Andre A Karlsen Tom H TH

The New England journal of medicine 20200617 16

<h4>Background</h4>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.<h4>Methods</h4>We conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory fail ...[more]

PMID: 32558485

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Project description:BackgroundPatients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities.MethodsPeripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery (n = 207) and validation (n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients.FindingsThe DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease.InterpretationWe identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2.FundingThe Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.

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Genomewide Association Study of Severe Covid-19 with Respiratory Failure.

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Genomewide Association Study of Severe Covid-19 with Respiratory Failure.

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