Influence of HLA Class I and II Polymorphisms on COVID-19 Severity in a South Brazilian Population

TL;DR

This study explores how variations in HLA genes affect the severity of COVID-19 in a Brazilian population, finding that certain HLA alleles are linked to either protection or increased risk.

Contribution

The study identifies specific HLA class II alleles associated with protection or risk for severe/critical COVID-19 outcomes in a South Brazilian population.

Findings

The DRB1*11 allelic group is associated with protection against severe and critical COVID-19.

The DRB1*15 allelic group is associated with increased risk of severe and critical disease.

In silico analysis shows DRB1*15 has higher binding affinity to SARS-CoV-2 non-structural proteins.

Abstract

The high variability of human leukocyte antigen (HLA) genes results in each molecule having distinct antigenic peptide binding capacities, potentially influencing the immune response to SARS-CoV-2. This study aimed to investigate associations between HLA class I (A, B) and class II (DRB1) polymorphisms and COVID-19 severity in a South Brazilian population, and to evaluate the binding affinity of alleles to viral peptides. A cross-sectional study included 503 unvaccinated patients with RT-qPCR-confirmed COVID-19: 145 non-severe, 129 severe, and 229 critical. HLA typing was performed using PCR-SSO and Luminex™ technology. The DRB1*11 allelic group was significantly associated with protection against severe and critical cases, while DRB1*15 was associated with increased risk; both remained significant after Bonferroni correction. Other allelic groups were associated with disease outcomes but lost significance after correction: B*49 and B*08 (risk); and B*37, B*50, and A*03 (protection). In silico analysis revealed that the DRB1*15 allele group showed a higher proportion of strong binders, mostly from non-structural proteins, while DRB1*11:01 binders, though fewer in number, were concentrated in the M protein. These results suggest functional differences in antigen presentation and reinforce the relevance of class II HLA, particularly DRB1, in modulating COVID-19 severity.

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