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

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.

The association of human leucocyte antigen (HLA) alleles with COVID‐19 severity: A systematic review and meta‐analysis

“… 40 As for HLA‐B*35, borderline significance was found for the negative association with fatal COVID‐19 in Saudi Arabian population, 41 while HLA‐B*35:01 allele also associated with shorter duration of hospitalisation. 32 Still, only HLA‐B*51:01 showed a statistically significant association with the severe disease in the present pooled analysis, while we found no evidence to support the protective effect of HLA‐B*35. Additionally, the present meta‐analysis confirmed the findings of Norin et al.…”

“…In the first two years of extensive research in the area of molecular genetics of COVID‐19, a significant number of association studies related to the disease severity, clinical course and the outcome of SARS‐CoV‐2 infection focused on host polymorphisms in HLA loci. 13 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 These studies were driven by previous results suggesting the involvement of HLA system in the regulation of the immune response to other viruses, as well as by the fine regulation of peptide‐binding properties by the extreme polymorphic feature of HLA loci. 61 , 62 …”

“…Based on this hypothesis, a relatively large number of studies investigated the role of HLA class I and class II alleles as predictors of COVID‐19 clinical course and the disease outcome. 13 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 However, their results varied significantly, possibly due to the differences in the study designs, severity‐based classification criteria, ethnicity of participants, or other factors with potential confounding effects. The observed heterogeneity between these studies makes it difficult to comprehensively assess the impact of allelic variants on disease severity.…”

Prognostic markers for the clinical course in the blood of patients with SARS-CoV-2 infection

“…Antibody determination was performed using two serological lateral ow assays as described before 10,20 .…”

“…Through its essential role in distinguishing between endogenous and exogenous cells, the HLA system plays a crucial role in the human immune response 9,10 . Therefore, genetic polymorphisms of Human Leukocyte Antigen (HLA) alleles appear to in uence the clinical course of patients infected with various RNA viruses, resulting in either protection or enhanced viral persistence 11 .…”