Weiner January, Suwalski Phillip, Holtgrewe Manuel, Rakitko Alexander, Thibeault Charlotte, Müller Melina, Patriki Dimitri, Quedenau Claudia, Krüger Ulrike, Ilinsky Valery, Popov Iaroslav, Balnis Joseph, Jaitovich Ariel, Helbig Elisa T, Lippert Lena J, Stubbemann Paula, Real Luis M, Macías Juan, Pineda Juan A, Fernandez-Fuertes Marta, Wang Xiaomin, Karadeniz Zehra, Saccomanno Jacopo, Doehn Jan-Moritz, Hübner Ralf-Harto, Hinzmann Bernd, Salvo Mauricio, Blueher Anja, Siemann Sandra, Jurisic Stjepan, Beer Juerg H, Rutishauser Jonas, Wiggli Benedikt, Schmid Hansruedi, Danninger Kathrin, Binder Ronald, Corman Victor M, Mühlemann Barbara, Arjun Arkal Rao, Fragiadakis Gabriela K, Mick Eran, Comet Consortium, Calfee Carolyn S, Erle David J, Hendrickson Carolyn M, Kangelaris Kirsten N, Krummel Matthew F, Woodruff Prescott G, Langelier Charles R, Venkataramani Urmila, García Federico, Zyla Joanna, Drosten Christian, Alice Braun, Jones Terry C, Suttorp Norbert, Witzenrath Martin, Hippenstiel Stefan, Zemojtel Tomasz, Skurk Carsten, Poller Wolfgang, Borodina Tatiana, Pa-Covid Study Group, Ripke Stephan, Sander Leif E, Beule Dieter, Landmesser Ulf, Guettouche Toumy, Kurth Florian, Heidecker Bettina
Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Unit Bioinformatics Berlin, DE 10178, Germany.
Department of Cardiology, Charite Universitaetsmedizin Berlin, DE 12203, Germany.
EClinicalMedicine. 2021 Oct;40:101099. doi: 10.1016/j.eclinm.2021.101099. Epub 2021 Sep 2.
Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors that affect individual immune response to SARS-CoV-2. We sought to evaluate this hypothesis by conducting a multicenter study using HLA sequencing.
We analyzed the association between COVID-19 severity and HLAs in 435 individuals from Germany ( = 135), Spain ( = 133), Switzerland ( = 20) and the United States ( = 147), who had been enrolled from March 2020 to August 2020. This study included patients older than 18 years, diagnosed with COVID-19 and representing the full spectrum of the disease. Finally, we tested our results by meta-analysing data from prior genome-wide association studies (GWAS).
We describe a potential association of HLA-C04:01 with severe clinical course of COVID-19. Carriers of HLA-C04:01 had twice the risk of intubation when infected with SARS-CoV-2 (risk ratio 1.5 [95% CI 1.1-2.1], odds ratio 3.5 [95% CI 1.9-6.6], adjusted -value = 0.0074). These findings are based on data from four countries and corroborated by independent results from GWAS. Our findings are biologically plausible, as HLA-C*04:01 has fewer predicted bindings sites for relevant SARS-CoV-2 peptides compared to other HLA alleles.
HLA-C*04:01 carrier state is associated with severe clinical course in SARS-CoV-2. Our findings suggest that HLA class I alleles have a relevant role in immune defense against SARS-CoV-2.
Funded by Roche Sequencing Solutions, Inc.
自2019冠状病毒病（COVID-19）大流行开始以来，确定导致严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染患者出现严重临床病程的病理生理特征的紧迫性日益增加。人类白细胞抗原等位基因（HLA）被认为是影响个体对SARS-CoV-2免疫反应的潜在遗传宿主因素。我们试图通过开展一项使用HLA测序的多中心研究来评估这一假设。
我们分析了2020年3月至2020年8月期间招募的来自德国（n = 135）、西班牙（n = 133）、瑞士（n = 20）和美国（n = 147）的435名个体中COVID-19严重程度与HLA之间的关联。这项研究纳入了年龄超过18岁、被诊断为COVID-19且代表该疾病全谱的患者。最后，我们通过对先前全基因组关联研究（GWAS）的数据进行荟萃分析来检验我们的结果。
我们描述了HLA-C04:01与COVID-19严重临床病程之间的潜在关联。HLA-C04:01携带者在感染SARS-CoV-2时插管风险增加一倍（风险比1.5[95%CI 1.1 - 2.1]，优势比3.5[95%CI 1.9 - 6.6]，校正P值 = 0.0074）。这些发现基于来自四个国家的数据，并得到了GWAS独立结果的证实。我们的发现具有生物学合理性，因为与其他HLA等位基因相比，HLA-C*04:01与相关SARS-CoV-2肽的预测结合位点较少。
HLA-C*04:01携带者状态与SARS-CoV-2的严重临床病程相关。我们的发现表明HLA I类等位基因在针对SARS-CoV-2的免疫防御中具有重要作用。
由罗氏测序解决方案公司资助
