Association of HLA Class I Genotypes With Severity of Coronavirus Disease-19

Abstract

Human leukocyte antigen (HLA) class I molecules play a crucial role in the development of a specific immune response to viral infections by presenting viral peptides at the cell surface where they will be further recognized by T cells. In the present manuscript, we explored whether HLA class I genotypes can be associated with the critical course of Coronavirus Disease-19 by searching possible connections between genotypes of deceased patients and their age at death. HLA-A, HLA-B, and HLA-C genotypes of n = 111 deceased patients with COVID-19 (Moscow, Russia) and n = 428 volunteers were identified with next-generation sequencing. Deceased patients were split into two groups according to age at the time of death: n = 26 adult patients aged below 60 and n = 85 elderly patients over 60. With the use of HLA class I genotypes, we developed a risk score (RS) which was associated with the ability to present severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) peptides by the HLA class I molecule set of an individual. The resulting RS was significantly higher in the group of deceased adults compared to elderly adults [p = 0.00348, area under the receiver operating characteristic curve (AUC ROC = 0.68)]. In particular, presence of HLA-A^*01:01 allele was associated with high risk, while HLA-A^*02:01 and HLA-A^*03:01 mainly contributed to low risk. The analysis of patients with homozygosity strongly highlighted these results: homozygosity by HLA-A^*01:01 accompanied early deaths, while only one HLA-A^*02:01 homozygote died before 60 years of age. Application of the constructed RS model to an independent Spanish patients cohort (n = 45) revealed that the score was also associated with the severity of the disease. The obtained results suggest the important role of HLA class I peptide presentation in the development of a specific immune response to COVID-19.

Keywords: COVID-19; HLA class I; MHC class I; SARS-CoV-2; peptide presentation.

Figure 1

Distribution of HLA-A, HLA-B, HLA-C alleles in cohorts of deceased COVID-19 patients and the control group. Alleles with frequency over 5% in at least one of three considered groups are presented.

Figure 2

Hierarchical clustering of HLA-A, HLA-B, HLA-C gene alleles and SARS-CoV-2 peptides according to binding affinity matrix. Shades of green in vertical stripes and percents in brackets represent frequency of an allele in the control group. Zero percents refer to rare alleles found only in the group of deceased patients.

Figure 3

Contingency table of allele counts in the control group. Alleles with frequency over 5% in the control group are presented.

Figure 4

Risk score (RS) separates groups of adult and elderly patients. (A) Distribution of RS in adult, elderly and control patient groups. (B) Receiver operating characteristic curve for RS separating patients from adult and elderly groups. (C) Empirical distribution function of RS in three patient groups. Vertical dotted lines at RS = 41 and RS = 89 define ranges for three RS groups. (D) Distribution of three patient groups over low, medium and high RS.

Figure 5

Risk score (RS) in groups of severe, moderate, and mild COVID-19 patients from the Spanish cohort.