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The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis

By David Ellinghaus, Frauke Degenhardt, Luis Bujanda, Maria Buti, Agustin Albillos, Pietro Invernizzi, Javier Fernandez, Daniele Prati, Guido Baselli, Rosanna Asselta, Marit Maehle Grimsrud, Chiara Milani, Fatima Aziz, Jan Kassens, Sandra May, Mareike Wendorff, Lars Wienbrandt, Florian Uellendahl-Werth, Tenghao Zheng, Xiaoli Yi, Raul de Pablo, Adolfo Garrido Chercoles, Adriana Palom, Alba-Estela Garcia-Fernandez, Francisco Rodriguez-Frias, Alberto Zanella, Alessandra Bandera, Alessandro Protti, Alessio Aghemo, Ana Lleo de Nalda, Andrea Biondi, Andrea Caballero-Garralda, Andrea Gori, Anja Tanck, Anna Latiano, Anna Ludovica Fracanzani, Anna Peschuck, Antonio Julia, Antonio Pesenti, Antonio Voza, David Jimenez, Beatriz Mateos, Beatriz Nafria Jimenez, Carmen Quereda, Claudio Angelini, Cristina Cea, Aurora Solier, David Pestana, Elena Sandoval, Elvezia Maria Paraboschi, Enrique Navas, Ferruccio Ceriotti, Filippo Martinelli-Boneschi, Flora Peyvandi, Francesco Blasi, Luis Tellez, Albert Blanco-Grau, Giacomo Grasselli, Giorgio Costantino, Giulia Cardamone, Giuseppe Foti, Serena Aneli, Hayato Kurihara, Hesham ElAbd, Ilaria My, Javier Martin, Jeanette Erdmann, Jose Ferrusquia-Acosta, Koldo Garcia-Etxebarria, Laura Izquierdo-Sanchez, Laura Rachele Bettini, Leonardo Terranova, Leticia Moreira, Luigi Santoro, Luigia Scudeller, Francisco Mesonero, Luisa Roade, Marco Schaefer, Maria Carrabba, Maria del Mar Riveiro Barciela, Maria Eloina Figuera Basso, Maria Grazia Valsecchi, Maria Hernandez-Tejero, Marialbert Acosta-Herrera, Mariella D'Angio, Marina Baldini, Marina Cazzaniga, Martin Schulzky, Maurizio Cecconi, Michael Wittig, Michele Ciccarelli, Miguel Rodriguez-Gandia, Monica Bocciolone, Monica Miozzo, Nicole Braun, Nilda Martinez, Orazio Palmieri, Paola Faverio, Paoletta Preatoni, Paolo Bonfanti, Paolo Omodei, Paolo Tentorio, Pedro Castro, Pedro M. Rodrigues, Aaron Blandino Ortiz, Ricard Ferrer, Roberta Gualtierotti, Rosa Nieto, Salvatore Badalamenti, Sara Marsal, Giuseppe Matullo, Serena Pelusi, Valter Monzani, Tanja Wesse, Tomas Pumarola, Valeria Rimoldi, Silvano Bosari, Wolfgang Albrecht, Wolfgang Peter, Manuel Romero Gomez, Mauro D'Amato, Stefano Duga, Jesus M Banales, Johannes Roksund Hov, Trine Folseraas, Luca Valenti, Andre Franke, Tom Hemming Karlsen

Posted 02 Jun 2020
medRxiv DOI: 10.1101/2020.05.31.20114991

Background. Respiratory failure is a key feature of severe Covid-19 and a critical driver of mortality, but for reasons poorly defined affects less than 10% of SARS-CoV-2 infected patients. Methods. We included 1,980 patients with Covid-19 respiratory failure at seven centers in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe (Milan, Monza, Madrid, San Sebastian and Barcelona) for a genome-wide association analysis. After quality control and exclusion of population outliers, 835 patients and 1,255 population-derived controls from Italy, and 775 patients and 950 controls from Spain were included in the final analysis. In total we analyzed 8,582,968 single-nucleotide polymorphisms (SNPs) and conducted a meta-analysis of both case-control panels. Results. We detected cross-replicating associations with rs11385942 at chromosome 3p21.31 and rs657152 at 9q34, which were genome-wide significant (P<5x10-8) in the meta-analysis of both study panels, odds ratio [OR], 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.14x10-10 and OR 1.32 (95% CI, 1.20 to 1.47; P=4.95x10-8), respectively. Among six genes at 3p21.31, SLC6A20 encodes a known interaction partner with angiotensin converting enzyme 2 (ACE2). The association signal at 9q34 was located at the ABO blood group locus and a blood-group-specific analysis showed higher risk for A-positive individuals (OR=1.45, 95% CI, 1.20 to 1.75, P=1.48x10-4) and a protective effect for blood group O (OR=0.65, 95% CI, 0.53 to 0.79, P=1.06x10-5). Conclusions. We herein report the first robust genetic susceptibility loci for the development of respiratory failure in Covid-19. Identified variants may help guide targeted exploration of severe Covid-19 pathophysiology.

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