Association of HLA genotypes, AB0 blood type and chemokine receptor 5 mutant CD195 with the clinical course of COVID-19

Johannes C Fischer, Albrecht G Schmidt, Edwin Bölke*, Markus Uhrberg, Verena Keitel, Torsten Feldt, Björn Jensen, Dieter Häussinger, Ortwin Adams, E Marion Schneider, Vera Balz, Jürgen Enczmann, Jutta Rox, Derik Hermsen, Karin Schulze-Bosse, Detlef Kindgen-Milles, Wolfram Trudo Knoefel, Martijn van Griensven, Jan Haussmann, Balint TamaskovicsChristian Plettenberg, Kathrin Scheckenbach, Stefanie Corradini, Alessia Pedoto, Kitti Maas, Livia Schmidt, Olaf Grebe, Irene Esposito, Anja Ehrhardt, Matthias Peiper, Bettina Alexandra Buhren, Christian Calles, Andreas Stöhr, Artur Lichtenberg, Noemi F Freise, Matthias Lutterbeck, Amir Rezazadeh, Wilfried Budach, Christiane Matuschek

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


BACKGROUND: COVID-19, the pandemic disease caused by infection with SARS-CoV-2, may take highly variable clinical courses, ranging from symptom-free and pauci-symptomatic to fatal disease. The goal of the current study was to assess the association of COVID-19 clinical courses controlled by patients' adaptive immune responses without progression to severe disease with patients' Human Leukocyte Antigen (HLA) genetics, AB0 blood group antigens, and the presence or absence of near-loss-of-function delta 32 deletion mutant of the C-C chemokine receptor type 5 (CCR5).

PATIENT AND METHODS: An exploratory observational study including 157 adult COVID-19 convalescent patients was performed with a median follow-up of 250 days. The impact of different HLA genotypes, AB0 blood group antigens, and the CCR5 mutant CD195 were investigated for their role in the clinical course of COVID-19. In addition, this study addressed levels of severity and morbidity of COVID-19. The association of the immunogenetic background parameters were further related to patients' humoral antiviral immune response patterns by longitudinal observation.

RESULTS: Univariate HLA analyses identified putatively protective HLA alleles (HLA class II DRB1*01:01 and HLA class I B*35:01, with a trend for DRB1*03:01). They were associated with reduced durations of disease instead decreased (rather than increased) total anti-S IgG levels. They had a higher virus neutralizing capacity compared to non-carriers. Conversely, analyses also identified HLA alleles (HLA class II DQB1*03:02 und HLA class I B*15:01) not associated with such benefit in the patient cohort of this study. Hierarchical testing by Cox regression analyses confirmed the significance of the protective effect of the HLA alleles identified (when assessed in composite) in terms of disease duration, whereas AB0 blood group antigen heterozygosity was found to be significantly associated with disease severity (rather than duration) in our cohort. A suggestive association of a heterozygous CCR5 delta 32 mutation status with prolonged disease duration was implied by univariate analyses but could not be confirmed by hierarchical multivariate testing.

CONCLUSION: The current study shows that the presence of HLA class II DRB1*01:01 and HLA class I B*35:01 is of even stronger association with reduced disease duration in mild and moderate COVID-19 than age or any other potential risk factor assessed. Prospective studies in larger patient populations also including novel SARS-CoV-2 variants will be required to assess the impact of HLA genetics on the capacity of mounting protective vaccination responses in the future.

Original languageEnglish
Article number107
Number of pages13
JournalEuropean Journal of Medical Research
Issue number1
Publication statusPublished - 16 Sept 2021


  • SARS-CoV-2
  • HLA class I genotypes
  • ABO blood group
  • Chemokine receptor
  • CCR5
  • Neutralizing antibodies
  • COVID-19
  • Clinical course

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