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.

Anahit Hovhannisyan,Rubina Arakelyan,Alina Sirunyan,Levon Yepiskoposyan,Sevak Avagyan,Vergine Madelian,Zorayr Manukyan,Frieda Jordan,Karine R Mayilyan,Mihran Nazaretyan,Armine Hyussyan

doi:10.3389/fimmu.2022.769900

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*51:01 carriage [odds ratio (OR)=0.48 (0.28-0.80), Pbonf <0.036] is protective against severe COVID-19. Contrary, the HLA-C*04:01 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*04:01 and age was secondary to a stronger association between HLA-C*04:01 and disease severity. However, HLA-C*04:01 exerted a sex-dependent differential distribution between clinical subgroups [females: P<0.0012; males: P=0.48]. The comparison of HLA-C*04:01 frequency between subgroups and 2,781 Armenian controls revealed a significant incidence of HLA-C*04:01 deficiency in asymptomatic COVID-19. HLA-C*04:01 homozygous genotype in patients blueprinted a decrease in heterozygosity of HLA-B and HLA class-I loci. In HLA-C*04:01 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*04:01, 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*04:01 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%).

Highlights

The novel coronavirus disease COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged at unprecedented scale and ferocity, putting enormous pressure on health systems globally
We found that the association of HLA-C*04:01 genotype with the age in the COVID-19 cases was secondary to the association between the genotype and the COVID-19 severity characteristics (HLA-C*04:01 association with age conditioned for the disease severity, P=0.13)
Based on the conjoint approach of HLA classical loci genotype and allelic distribution analyses between Armenian population controls and COVID-19 cases, as well as between patients with different clinical phenotypes, we discovered an age-related protective effect of the HLA-B*51:01 carriage against COVID19 severity

Summary

Introduction

The novel coronavirus disease COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged at unprecedented scale and ferocity, putting enormous pressure on health systems globally. As of 31 August 2021, according to the World Health Organization, the cumulative number of coronavirus-infected patients identified is 216,867,420 [1]. In terms of the clinical course of the disease, its spectrum can range from asymptomatic to severe manifestation, with acute respiratory failure leading to death in some cases [2, 3]. The early reports on the COVID-19 clinical characteristics indicate that up to 20% of patients required admission to critical care, such as intensive care unit (ICU), and prolonged support by mechanical ventilation in case of respiratory failure. Age and sex of individuals, environmental and socioeconomic factors are known to affect both the susceptibility and the severity of COVID-19 [5, 6]. Knowledge on the influence of the host genetic profile on the susceptibility and outcome of the disease is being continuously generated

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Conclusion