Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01
January Weiner, Phillip Suwalski, Manuel Holtgrewe, Alexander Rakitko, Charlotte Thibeault, Melina Müller, Dimitri Patriki, Claudia Quedenau, Ulrike Krüger, Valery Ilinsky, Iaroslav Popov, Joseph Balnis, Ariel Jaitovich, Elisa T. Helbig, Lena J. Lippert, Paula Stubbemann, Luís Miguel Real, Juan Macı́as, Juan A. Pineda, Marta Fernández‐Fuertes, Xiaomin Wang, Zehra Karadeniz, Jacopo Saccomanno, Jan-Moritz Doehn, Ralf‐Harto Hübner, Bernd Hinzmann, Salvo Mauricio, Anja Blueher, Sandra Siemann, Stjepan Jurisic, Jürg H. Beer, Jonas Rutishauser, Benedikt Wiggli, Hansruedi Schmid, Kathrin Danninger, Ronald Binder, Victor M. Corman, Barbara Mühlemann, Rao Arjun Arkal, Gabriela K. Fragiadakis, Eran Mick, Carolyn S. Calfee, David J. Erle, Carolyn M. Hendrickson, Kirsten N. Kangelaris, Matthew F. Krummel, Prescott G. Woodruff, Charles Langelier, Urmila Venkataramani, Féderico García, Joanna Żyła, Christian Drosten, Alice Braun, Terry C. Jones, Norbert Suttorp, Martin Witzenrath, Stefan Hippenstiel, Tomasz Żemojtel, Carsten Skurk, Wolfgang Poller, Tatiana Borodina, Study Group Pa-COVID, Stephan Ripke, Leif Erik Sander, Dieter Beule, Ulf Landmesser, Toumy Guettouche, Florian Kurth, Bettina Heidecker
Abstract
Background 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. Methods We analyzed the association between COVID-19 severity and HLAs in 435 individuals from Germany ( n = 135), Spain ( n = 133), Switzerland ( n = 20) and the United States ( n = 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). Findings We describe a potential association of HLA-C*04:01 with severe clinical course of COVID-19. Carriers of HLA-C*04:01 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 p -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. Interpretation 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. Funding Funded by Roche Sequencing Solutions, Inc.