Association of HLA genotypes, AB0 blood type and chemokine receptor 5 mutant CD195 with the clinical course of COVID-19
Authors: Fischer Johannes C. , Schmidt Albrecht G. , Bölke Edwin , Uhrberg Markus , Keitel Verena , Feldt Torsten , Jensen Björn , Häussinger Dieter , Adams Ortwin , Schneider E. Marion , Balz Vera , Enczmann Jürgen , Rox Jutta , Hermsen Derik , Schulze-Bosse Karin , Kindgen-Milles Detlef , Knoefel Wolfram Trudo , van Griensven Martijn , Haussmann Jan , Tamaskovics Balint , Plettenberg Christian , Scheckenbach Kathrin , Corradini Stefanie , Pedoto Alessia , Maas Kitti , Schmidt Livia , Grebe Olaf , Esposito Irene , Ehrhardt Anja , Peiper Matthias , Buhren Bettina Alexandra , Calles Christian , Stöhr Andreas , Lichtenberg Artur , Freise Noemi F. , Lutterbeck Matthias , Rezazadeh Amir , Budach Wilfried , Matuschek Christiane 
Published: September 2021

Abstract
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.