Korean J Transplant.  2022 Nov;36(Supple 1):S69. 10.4285/ATW2022.F-1856.

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

• Jordan F
• Hovhannisyan A
• Madelian V
• Avagyan S
• Nazaretyan M
• Hyussyan A
• Arakelyan R
• Manukyan Z
• Yepiskoposyan L
• Mayilyan K

• KMID: 2535487
• DOI: http://doi.org/10.4285/ATW2022.F-1856

Abstract

The SARS-CoV-2 coronavirus infection has become a global health concern, causing the COVID-19 pandemic. The disease symp-toms and outcomes depend on the host immunity, in which the HLA molecules play a distinct role. The present study aimed at detecting associations between HLA alleles and COVID-19 susceptibility and severity in Armenians. The study included 299 SARS-CoV-2 infected patients (75 asymptomatic, 102 mild, 122 severe). To compare the allelic frequency profiles of patient groups with those specific to the general population, we used HLA data of 2,781 registered donors at the Armenian BMDR. This group was used as a control cohort for age-genotype and allele frequency analyses. Based on the conjoint approach of HLA classical loci genotype and allelic distribution analyses between Armenian population controls and COVID-19 cases we discov-ered an age-related protective effect of the HLA-B*51:01 carriage against COVID-19 severity. In contrast HLA-C*04:01 allelic-load contributes to the risk for severe COVID-19 independently of age and classical HLA variables. The HLA-C*04:01 association with COVID-19 manifestation is rather in concert with the female gender and older age. Along with the expected significant decrease in cumulative heterozygosity of HLA class I loci, we report a previously undescribed decrease in heterozygosity of the HLA-B locus blueprinted by the HLA-C*04:01 homozygous genotype. In patients with mild to severe COVID-19, due to the high preva-lence of HLA-C*04:01, these effects provide a decrease of the HLA class I loci heterozygosity and a down-modulation of the predicted HLA class I ability to recognize SARS-CoV-2 peptides. The genomic number of HLA-C*04:01 allele and demographic variables compose the model, in which >15% potential share in the detection of cases with adverse clinical phenotypes belongs to HLA-C*04:01. The results of the study suggest a putative role of HLA-C genetic variation in the development of a specific im-mune response to COVID-19.