<scp>HLA</scp> ‐B Serine 116 Confers Protection Against Severe <scp>COVID</scp> ‐19 in a Cohort From Rio de Janeiro, Brazil

COVID-19 is a respiratory disease caused by SARS-CoV-2, in which severe outcomes are primarily driven by an exacerbated immune response. The HLA region has been extensively investigated in COVID-19 due to its central role in the immune response, although genetic associations vary across populations. Here, the association of HLA genetic variability with COVID-19 severe respiratory outcomes was investigated in an admixed population from Rio de Janeiro, Brazil. Results of a comparative study between mild and severe COVID-19 cases involving 306 individuals have suggested risk associations with severe COVID-19 for the HLA-DPB1*13:01 allele (OR = 3.42, 95% CI = 1.05-11.16, p = 0.041) and the HLA-B*39 allele group (OR = 3.26, 95% CI = 1.16-9.13, p = 0.024), although statistical significance was lost after FDR adjustment for multiple comparisons (adjusted p > 0.05). Amino acid analyses showed that a serine at position 116 of HLA-B conferred protection against severe COVID-19 (OR = 0.4774, 95% CI = 0.28-0.81, p = 0.006, adjusted p = 0.031). In silico analysis using the NetMHCpan tool predicted that this residue, located in the HLA-B peptide-binding groove, has enhanced binding affinity to immunodominant SARS-CoV-2 epitopes, suggesting a functional mechanism underlying the observed protection. The association of single nucleotide variants at the HLA region was also investigated, and no statistically significant association was found. Results obtained in the present study underscore the importance of HLA in COVID-19 severity, likely mediated by its influence on viral peptide presentation, and advance our understanding of the genetic underpinnings of severe disease in admixed populations.