Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01

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; Wolfgang, Poller; Borodina, Tatiana; Pa-COVID, Study Group; Ripke, Stephan; Sander, Leif E; Beule, Dieter; Landmesser, Ulf; Guettouche, Toumy; Kurth, Florian; Heidecker, Bettina

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.