Nakanishi Tomoko, Pigazzini Sara, Degenhardt Frauke, Cordioli Mattia, Butler-Laporte Guillaume, Maya-Miles Douglas, Nafría-Jiménez Beatriz, Bouysran Youssef, Niemi Mari, Palom Adriana, Ellinghaus David, Khan Atlas, Martínez-Bueno Manuel, Rolker Selina, Amitano Sara, Tato Luisa Roade, Fava Francesca, Spinner Christoph D, Prati Daniele, Bernardo David, Garcia Federico, Darcis Gilles, Fernández-Cadenas Israel, Holter Jan Cato, Banales Jesus, Frithiof Robert, Kiryluk Krzysztof, Duga Stefano, Asselta Rosanna, Pereira Alexandre C, Romero-Gómez Manuel, Bujanda Luis, Hov Johannes R, Migeotte Isabelle, Renieri Alessandra, Planas Anna M, Ludwig Kerstin U, Buti Maria, Rahmouni Souad, Alarcón-Riquelme Marta E, Schulte Eva C, Franke Andre, Karlsen Tom H, Valenti Luca, Zeberg Hugo, Richards J Brent, Ganna Andrea
Institute for Molecular Medicine Finland, Univerisity of Helsinki, Helsinki, Finland.
Department of Human Genetics, McGill University, Montréal, Québec, Canada.
medRxiv. 2021 Mar 12:2021.03.07.21252875. doi: 10.1101/2021.03.07.21252875.
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.
在年轻成年人中，新冠病毒病（COVID-19）的预后存在很大差异，其中一些差异可能归因于遗传易感性。我们利用一个大型国际多中心联盟的个体水平数据，对COVID-19严重程度的主要遗传风险因素及其年龄依赖性效应的临床意义进行了描述。
COVID-19主要的常见遗传风险因素是3号染色体位点，由标记rs10490770标记。我们汇总了来自9个国家17个队列的13424例COVID-19阳性患者（N=6689例住院患者）的个体水平数据，以评估该遗传标记与死亡率、COVID-19相关并发症和实验室检查值之间的关联。接下来，我们研究了这些关联的强度是否因年龄而异，以及是否独立于已知的COVID-19临床风险因素。
我们发现，rs10490770风险等位基因携带者全因死亡率（风险比[HR]1.4，95%置信区间[CI]1.2-1.6）和COVID-19相关死亡率（HR 1.5，95%CI 1.3-1.8）的风险增加。风险等位基因携带者发生几种COVID-19并发症的几率增加：严重呼吸衰竭（优势比[OR]2.0，95%CI 1.6-2.6）、静脉血栓栓塞（OR 1.7，95%CI 1.2-2.4）和肝损伤（OR 1.6，95%CI 1.2-2.0）。与60岁以上人群相比，60岁及以下的风险等位基因携带者死亡或发生严重呼吸衰竭的几率更高（OR 2.6，95%CI 1.8-3.9），而60岁以上人群的OR为1.5（95%CI 1.3-1.9，交互p值=0.04）。在60岁及以下死亡或发生严重呼吸COVID-19结局的个体中，我们发现31.8%（95%CI 27.6-36.2%）是风险变异携带者，而未发生这些结局的个体中这一比例为13.9%（95%CI 12.6-15.2%）。纳入风险等位基因后，60岁及以下人群死亡或发生严重呼吸衰竭的预测准确性提高（曲线下面积[AUC]0.82对0.84，p=0.016），且rs10490770风险等位基因的预测能力与大多数已确立的临床风险因素相似或更好。
3号染色体上主要的常见COVID-19风险位点与发病和死亡风险增加相关，且在60岁及以下个体中更为明显。对COVID-19严重程度的影响与大多数已确立的风险因素相似或更大，提示对临床风险管理具有潜在意义。
每个参与队列单独获得资金。
