Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality
Nakanishi, Tomoko (Japan Society for the Promotion of Science, Tokyo)
Pigazzini, Sara (University of Milano-Bicocca, Milano)
Degenhardt, Frauke (Universitätsklinikum Schleswig-Holstein (Alemanya))
Cordioli, Mattia (Univerisity of Helsinki)
Butler-Laporte, Guillaume (McGill University, Montréal, Québec)
Maya-Miles, Douglas (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Nafría-Jiménez, Beatriz (Osakidetza-Servicio Vasco de Salud, Donostia)
Bouysran, Youssef (Université Libre de Bruxelles)
Niemi, Mari (Univerisity of Helsinki)
Palom, Adriana (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Ellinghaus, David (University of Copenhagen)
Khan, Atlas (Columbia University, New York)
Martínez-Bueno, Manuel (Universidad de Granada)
Rolker, Selina (University Hospital Bonn (Bonn, Alemanya))
Amitano, Sara (Azienda Ospedaliero-Universitaria Senese)
Roade, Luisa (Universitat Autònoma de Barcelona. Departament de Medicina)
Fava, Francesca (University of Siena, Italy)
Spinner, Christoph D. (Technical University of Munich)
Prati, Daniele (Università degli Studi di Milano)
Bernardo, D (Universidad de Valladolid)
Garcia, Federico (Instituto de Investigación Sanitaria de Granada)
Darcis, Gilles (Liège University Hospital (Bèlgica))
Fernandez-Cadenas, Israel (Institut d'Investigació Biomèdica Sant Pau)
Holter, Jan Cato (Institute of Clinical Medicine, University of Oslo, Oslo, Norway)
Banales, Jesus (Universidad del País Vasco)
Frithiof, Robert (Uppsala University, Sweden)
Kiryluk, Krzysztof (Columbia University, New York)
Duga, Stefano (Istituto di Ricovero e Cura A Carattere Scientifico (IRCCS))
Asselta, Rosanna (Istituto di Ricovero e Cura A Carattere Scientifico (IRCCS))
Pereira, Alexandre C. (Universidade de São Paulo)
Romero-Gómez, Manuel (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Bujanda, Luis (Universidad del País Vasco)
Hov, Johannes R.. (Oslo University Hospital (Oslo, Noruega))
Migeotte, Isabelle (Fonds de la Recherche Scientifique (FNRS), Brussels)
Renieri, Alessandra (University of Siena, Italy)
Planas, Anna M. (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Ludwig, Kerstin U. (University Hospital Bonn (Bonn, Alemanya))
Buti, Maria (Universitat Autònoma de Barcelona. Departament de Medicina)
Rahmouni, Souad (University of Liege)
Alarcón-Riquelme, Marta E. (Karolinska Institutet (Estocolm, Suècia))
Schulte, Eva C. (Munich University. Medical Center)
Franke, Andre (University Hospital Schleswig-Holstein, Kiel)
Karlsen, Tom H. (Oslo University Hospital (Oslo, Noruega))
Valenti, Luca (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Milà, Itàlia))
Zeberg, Hugo (Max-Planck Institute for Evolutionary Anthropology, Leipzig, Germany)
Richards, J. Brent (King's College London)
Ganna, Andrea (Massachusetts General Hospital (Boston))

Date:	2021
Abstract:	There is considerable variability in COVID-19 outcomes amongst younger adults-and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium. The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors. We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2-1·6) and COVID-19 related mortality (HR 1·5, 95%CI 1·3-1·8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6), venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI 1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers, compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors. The major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality-and these are more pronounced amongst individuals ≤ 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management. Funding was obtained by each of the participating cohorts individually.
Grants:	European Commission 777377
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió de l'autor
Published in:	medRxiv, march 2021

DOI: 10.1101/2021.03.07.21252875
PMID: 33758887

40 p, 490.3 KB

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