HLA-C*04:01 Affects HLA Class I Heterozygosity and Predicted Affinity to SARS-CoV-2 Peptides, and in Combination With Age and Sex of Armenian Patients Contributes to COVID-19 Severity.

ABSTRACT

The novel SARS-CoV-2 coronavirus infection has become a global health concern, causing the COVID-19 pandemic. The disease symptoms and outcomes depend on the host immunity, in which the human leukocyte antigen (HLA) molecules play a distinct role. The HLA alleles have an inter-population variability, and understanding their link to the COVID-19 in an ethnically distinct population may contribute to personalized medicine. The present study aimed at detecting associations between common HLA alleles and COVID-19 susceptibility and severity in Armenians. In 299 COVID-19 patients (75 asymptomatic, 102 mild/moderate, 122 severe), the association between disease severity and classic HLA-I and II loci was examined. We found that the advanced age, male sex of patients, and sex and age interaction significantly contributed to the severity of the disease. We observed that an age-dependent effect of HLA-B*5101 carriage [odds ratio (OR)=0.48 (0.28-0.80), Pbonf <0.036] is protective against severe COVID-19. Contrary, the HLA-C*0401 allele, in a dose-dependent manner, was associated with a significant increase in the disease severity [OR (95% CI) =1.73 (1.20-2.49), Pbonf <0.021] and an advancing age (P<0.013). The link between HLA-C*0401 and age was secondary to a stronger association between HLA-C*0401 and disease severity. However, HLA-C*0401 exerted a sex-dependent differential distribution between clinical subgroups [females P<0.0012; males P=0.48]. The comparison of HLA-C*0401 frequency between subgroups and 2,781 Armenian controls revealed a significant incidence of HLA-C*0401 deficiency in asymptomatic COVID-19. HLA-C*0401 homozygous genotype in patients blueprinted a decrease in heterozygosity of HLA-B and HLA class-I loci. In HLA-C*0401 carriers, these changes translated to the SARS-CoV-2 peptide presentation predicted inefficacy by HLA-C and HLA class-I molecules, simultaneously enhancing the appropriate HLA-B potency. In patients with clinical manifestation, due to the high prevalence of HLA-C*0401, these effects provided a decrease of the HLA class-I heterozygosity and an ability to recognize SARS-CoV-2 peptides. Based on our observations, we developed a prediction model involving demographic variables and HLA-C*0401 allele for the identification of potential cases with the risk of hospitalization (the area under the curve (AUC) = 86.2%) or severe COVID-19 (AUC =71%).