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Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality.

The Journal of clinical investigation

Authors: Tomoko Nakanishi, Sara Pigazzini, Frauke Degenhardt, Mattia Cordioli, Guillaume Butler-Laporte, Douglas Maya-Miles, Luis Bujanda, Youssef Bouysran, Mari Ek Niemi, Adriana Palom, David Ellinghaus, Atlas Khan, Manuel Martínez-Bueno, Selina Rolker, Sara Amitrano, Luisa Roade Tato, Francesca Fava, Christoph D Spinner, Daniele Prati, David Bernardo, Federico Garcia, Gilles Darcis, Israel Fernández-Cadenas, Jan Cato Holter, Jesus M Banales, Robert Frithiof, Krzysztof Kiryluk, Stefano Duga, Rosanna Asselta, Alexandre C Pereira, Manuel Romero-Gómez, Beatriz Nafría-Jiménez, Johannes R Hov, Isabelle Migeotte, Alessandra Renieri, Anna M Planas, Kerstin U Ludwig, Maria Buti, Souad Rahmouni, Marta E Alarcón-Riquelme, Eva C Schulte, Andre Franke, Tom H Karlsen, Luca Valenti, Hugo Zeberg, J Brent Richards, Andrea Ganna

BackgroundThere is considerable variability in COVID-19 outcomes among younger adults, and some of this variation may be due to genetic predisposition.MethodsWe combined individual level data from 13,888 COVID-19 patients (n = 7185 hospitalized) from 17 cohorts in 9 countries to assess the association of the major common COVID-19 genetic risk factor (chromosome 3 locus tagged by rs10490770) with mortality, COVID-19-related complications, and laboratory values. We next performed metaanalyses using FinnGen and the Columbia University COVID-19 Biobank.ResultsWe found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (HR, 1.4; 95% CI, 1.2-1.7). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (OR, 2.1; 95% CI, 1.6-2.6), venous thromboembolism (OR, 1.7; 95% CI, 1.2-2.4), and hepatic injury (OR, 1.5; 95% CI, 1.2-2.0). Risk allele carriers age 60 years and younger had higher odds of death or severe respiratory failure (OR, 2.7; 95% CI, 1.8-3.9) compared with those of more than 60 years (OR, 1.5; 95% CI, 1.2-1.8; interaction, P = 0.038). Among individuals 60 years and younger who died or experienced severe respiratory failure, 32.3% were risk-variant carriers compared with 13.9% of those not experiencing these outcomes. This risk variant improved the prediction of death or severe respiratory failure similarly to, or better than, most established clinical risk factors.ConclusionsThe major common COVID-19 genetic risk factor is associated with increased risks of morbidity and mortality, which are more pronounced among individuals 60 years or younger. The effect was similar in magnitude and more common than most established clinical risk factors, suggesting potential implications for future clinical risk management.

PMID: 34597274

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