Human leukocyte antigen (HLA) genes with extreme diversity can make a contribution for individual variations to the immune response against SARS-COV-2 infection. This study aimed to explore the distributions of HLA class II alleles frequencies and their relations with disease severity in a group of Iranian COVID-19 patients. This prospective and case-control study was conducted on 144 COVID-19 patients including 46 cases with moderate form, 54 cases with severe and 44 cases with critical disease. HLA-DRB1 and –DQB1 allele families were determined by PCR-SSP method and compared between three groups of the patients and in comparison to 153 ethnic-matched healthy controls. The patients group showed lower frequencies of HLA-DRB1*15 (OR=0.57, P=0.06), DRB1*15∼DQB1*05 haplotype (P=0.04) and DRB1*15/DRB1*04 genotype (P=0.04) in compare with healthy controls. Moderate COVID-19 patients had higher frequencies of HLA-DRB1*04 (P=0.03), HLA-DRB1*10 (P=0.05) and DRB1*04/DRB1*11 genotype (P=0.01). Also, a higher significantly frequency of HLA-DRB1*03 allele group was observed in the critical patients versus controls (P=0.01). Multiple logistic regression analysis revealed that the presence of DRB1*04 allele group was negatively associated with development of severe and critical disease (OR: 0.289, P=0.005) . Our results indicate a possible contribution of some HLA class II alleles in disease severity and clinical features of COVID-19 disease.

An important number of studies have been conducted on the potential association between human leukocyte antigen (HLA) genes and COVID-19 susceptibility and severity since the beginning of the pandemic. However, case–control and peptide-binding prediction methods tended to provide inconsistent conclusions on risk and protective HLA alleles, whereas some researchers suggested the importance of considering the overall capacity of an individual’s HLA Class I molecules to present SARS-CoV-2-derived peptides. To close the gap between these approaches, we explored the distributions of HLA-A, -B, -C, and -DRB1 1st-field alleles in 142 Iranian patients with COVID-19 and 143 ethnically matched healthy controls, and applied in silico predictions of bound viral peptides for each individual’s HLA molecules. Frequency comparison revealed the possible predisposing roles of HLA-A*03, B*35, and DRB1*16 alleles and the protective effect of HLA-A*32, B*58, B*55, and DRB1*14 alleles in the viral infection. None of these results remained significant after multiple testing corrections, except HLA-A*03, and no allele was associated with severity, either. Compared to peptide repertoires of individual HLA molecules that are more likely population-specific, the overall coverage of virus-derived peptides by one’s HLA Class I molecules seemed to be a more prominent factor associated with both COVID-19 susceptibility and severity, which was independent of affinity index and threshold chosen, especially for people under 60 years old. Our results highlight the effect of the binding capacity of different HLA Class I molecules as a whole, and the more essential role of HLA-A compared to HLA-B and -C genes in immune responses against SARS-CoV-2 infection.