HLA-C * 04:01 is a Genetic Risk Allele for Severe Course of COVID-19

  1. Weiner January
  2. Suwalski Phillip
  3. Holtgrewe Manuel
  4. Thibeault Charlotte
  5. Melina Müller
  6. Patriki Dimitri
  7. Quedenau Claudia
  8. Ulrike Krüger
  9. T. Helbig Elisa
  10. Lippert Lena
  11. Stubbemann Paula
  12. Real Luis Miguel
  13. Sanchez Juan Macias
  14. A. Pineda Juan
  15. Fernandez-Fuertes Marta
  16. Wang Xiaomin
  17. Karadeniz Zehra
  18. Saccomanno Jacopo
  19. Doehn Jan-Moritz
  20. Hübner Ralf-Harto
  21. Hinzmann Bernd
  22. Salvo Mauricio
  23. Blueher Anja
  24. Siemann Sandra
  25. Jurisic Stjepan
  26. Beer Hansjuerg
  27. Rutishauser Jonas
  28. Wiggli Benedikt
  29. Schmid Hansruedi
  30. Danninger Kathrin
  31. Binder Ronald
  32. M. Victor Corman
  33. Mühlemann Barbara
  34. Braun Alice
  35. Ripke Stephan
  36. C. Jones Terry
  37. Suttorp Norbert
  38. Witzenrath Martin
  39. Hippenstiel Stefan
  40. Zemojtel Tomasz
  41. Skurk Carsten
  42. Poller Wolfgang
  43. Borodina Tatiana
  44. Pa-COVID Study Group
  45. E. Sander Leif
  46. Beule Dieter
  47. Landmesser Ulf
  48. Guettouche Toumy
  49. Kurth Florian
  50. Heidecker Bettina

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Abstract

Background

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing demand to identify predictors of 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. We sought to evaluate this hypothesis by conducting an international multicenter study using HLA sequencing with subsequent independent validation.

Methods

We analyzed a total of 332 samples. First, we enrolled 233 patients in Germany, Spain, and Switzerland for HLA and whole exome sequencing. Furthermore, we validated our results in a public data set (United States, n=99). Patients older than 18 years presenting with COVID-19 were included, representing the full spectrum of the disease. HLA candidate alleles were identified in the derivation cohort (n=92) and tested in two independent validation cohorts (n=240).

Results

We identified HLA-C* 04:01 as a novel genetic predictor for severe clinical course in COVID-19. Carriers of HLA-C* 04:01 had twice the risk of intubation when infected with SARS-CoV-2 (hazard ratio 2.1, adjusted p-value=0.0036). Importantly, these findings were successfully replicated in an independent data set. Furthermore, our findings are biologically plausible, as HLA-C* 04:01 has fewer predicted bindings sites with relevant SARS-CoV-2 peptides as compared to other HLA alleles. Exome sequencing confirmed findings from HLA analysis.

Conclusions

HLA-C* 04:01 carriage is associated with a twofold increased risk of intubation in patients infected with SARS-CoV-2. Testing for HLA-C* 04:01 could have clinical implications to identify high-risk patients and individualize management.

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  1. ScreenIT

    SciScore for 10.1101/2020.12.21.20248121: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementConsent: All patients with COVID-19, who provided informed consent and were 18 years or older were included.
    IRB: Ethics committee approval: Our protocol included blood samples obtained during routine clinically indicated venipunctures, which were then frozen at -80°C for subsequent deoxyribonucleic acid (DNA) extraction and sequencing.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    A limitation of this study was that in order to promptly respond to the COVID-19 pandemic with an international multi-center study, even patients with limited metadata were enrolled in this study. However, risk factors and clinical outcomes that we considered most relevant based on prior literature were collected and analyzed for all patients included in our cohorts. Reproducibility of our data in an entirely independent cohort in Albany, United States supports the robustness of our data despite this limitation.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a protocol registration statement.

    About SciScore

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  2. Version published to 10.1101/2020.12.21.20248121v1 on medRxiv