TY - JOUR
T1 - Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality
AU - Nakanishi, Tomoko
AU - Pigazzini, Sara
AU - Degenhardt, Frauke
AU - Cordioli, Mattia
AU - Butler-Laporte, Guillaume
AU - Maya-Miles, Douglas
AU - Nafría-Jiménez, Beatriz
AU - Bouysran, Youssef
AU - Niemi, Mari
AU - Palom, Adriana
AU - Ellinghaus, David
AU - Khan, Atlas
AU - Martínez-Bueno, Manuel
AU - Rolker, Selina
AU - Amitano, Sara
AU - Roade, Luisa
AU - Fava, Francesca
AU - Spinner, Christoph D.
AU - Prati, Daniele
AU - Bernardo, D
AU - Garcia, Federico
AU - Darcis, Gilles
AU - Fernandez-Cadenas, Israel
AU - Holter, Jan Cato
AU - Banales, Jesus
AU - Frithiof, Robert
AU - Kiryluk, Krzysztof
AU - Duga, Stefano
AU - Asselta, Rosanna
AU - Pereira, Alexandre C.
AU - Romero-Gómez, Manuel
AU - Bujanda, Luis
AU - Hov, Johannes R..
AU - Migeotte, Isabelle
AU - Renieri, Alessandra
AU - Planas, Anna M.
AU - Ludwig, Kerstin U.
AU - Buti, Maria
AU - Rahmouni, Souad
AU - Alarcón-Riquelme, Marta E.
AU - Schulte, Eva C.
AU - Franke, Andre
AU - Karlsen, Tom H.
AU - Valenti, Luca
AU - Zeberg, Hugo
AU - Richards, J. Brent
AU - Ganna, Andrea
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
U2 - 10.1101/2021.03.07.21252875
DO - 10.1101/2021.03.07.21252875
M3 - Article
C2 - 33758887
JO - medRxiv
JF - medRxiv
ER -