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


  • J. Weiner
  • P. Suwalski
  • M. Holtgrewe
  • A. Rakitko
  • C. Thibeault
  • M. Müller
  • D. Patriki
  • C. Quedenau
  • U. Krüger
  • V. Ilinsky
  • I. Popov
  • J. Balnis
  • A. Jaitovich
  • E.T. Helbig
  • L.J. Lippert
  • P. Stubbemann
  • L.M. Real
  • J. Macías
  • J.A. Pineda
  • M. Fernandez-Fuertes
  • X. Wang
  • Z. Karadeniz
  • J. Saccomanno
  • J.M. Doehn
  • R.H. Hübner
  • B. Hinzmann
  • M. Salvo
  • A. Blueher
  • S. Siemann
  • S. Jurisic
  • J.H. Beer
  • J. Rutishauser
  • B. Wiggli
  • H. Schmid
  • K. Danninger
  • R. Binder
  • V.M. Corman
  • B. Mühlemann
  • R. Arjun Arkal
  • G.K. Fragiadakis
  • E. Mick
  • C.S. Calfee
  • D.J. Erle
  • C.M. Hendrickson
  • K.N. Kangelaris
  • M.F. Krummel
  • P.G. Woodruff
  • C.R. Langelier
  • U. Venkataramani
  • F. García
  • J. Zyla
  • C. Drosten
  • A. Braun
  • T.C. Jones
  • N. Suttorp
  • M. Witzenrath
  • S. Hippenstiel
  • T. Zemojtel
  • C. Skurk
  • P. Wolfgang
  • T. Borodina
  • S. Ripke
  • L.E. Sander
  • D. Beule
  • U. Landmesser
  • T. Guettouche
  • F. Kurth
  • B. Heidecker


  • EClinicalMedicine


  • EClinicalMedicine 40: 101099


  • 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.