Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality
Author:
Nakanishi TomokoORCID, Pigazzini SaraORCID, Degenhardt Frauke, Cordioli MattiaORCID, Butler-Laporte GuillaumeORCID, Maya-Miles DouglasORCID, Nafría-Jiménez BeatrizORCID, Bouysran YoussefORCID, Niemi MariORCID, Palom AdrianaORCID, Ellinghaus DavidORCID, Khan AtlasORCID, Martínez-Bueno ManuelORCID, Rolker Selina, Amitano Sara, Tato Luisa RoadeORCID, Fava FrancescaORCID, Spinner Christoph D.ORCID, Prati DanieleORCID, Bernardo DavidORCID, Garcia Federico, Darcis GillesORCID, Fernández-Cadenas IsraelORCID, Holter Jan CatoORCID, Banales Jesus, Frithiof RobertORCID, Kiryluk KrzysztofORCID, Duga StefanoORCID, Asselta RosannaORCID, Pereira Alexandre CORCID, Romero-Gómez ManuelORCID, Bujanda Luis, Hov Johannes R.ORCID, Migeotte IsabelleORCID, Renieri AlessandraORCID, Planas Anna M.ORCID, Ludwig Kerstin U.ORCID, Buti MariaORCID, Rahmouni SouadORCID, Alarcón-Riquelme Marta E.ORCID, Schulte Eva C.ORCID, Franke Andre, Karlsen Tom HORCID, Valenti LucaORCID, Zeberg HugoORCID, Richards J. BrentORCID, Ganna AndreaORCID, ,
Abstract
AbstractBackgroundThere 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.MethodThe 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.FindingsWe 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.InterpretationThe 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.FundingFunding was obtained by each of the participating cohorts individually.
Publisher
Cold Spring Harbor Laboratory
Cited by
18 articles.
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