The association of human leucocyte antigen (HLA) alleles with COVID‐19 severity: A systematic review and meta‐analysis

Abstract

Due to their pivotal role in orchestrating the immune response, HLA loci were recognized as candidates for genetic association studies related to the severity of COVID‐19. Since the findings on the effects of HLA alleles on the outcome of SARS‐CoV‐2 infection remain inconclusive, we aimed to elucidate the potential involvement of genetic variability within HLA loci in the molecular genetics of COVID‐19 by classifying the articles according to different disease severity/outcomes and by conducting a systematic review with meta‐analysis. Potentially eligible studies were identified by searching PubMed, Scopus and Web of Science literature databases. A total of 28 studies with 13,073 participants were included in qualitative synthesis, while the results of 19 studies with 10,551 SARS‐CoV‐2‐positive participants were pooled in the meta‐analysis. According to the results of quantitative data synthesis, association with COVID‐19 severity or with the lethal outcome was determined for the following alleles and allele families: HLA‐A*01, HLA‐A*03, HLA‐A*11, HLA‐A*23, HLA‐A*31, HLA‐A*68, HLA‐A*68:02, HLA‐B*07:02, HLA‐B*14, HLA‐B*15, HLA‐B*40:02, HLA‐B*51:01, HLA‐B*53, HLA‐B*54, HLA‐B*54:01, HLA‐C*04, HLA‐C*04:01, HLA‐C*06, HLA‐C*07:02, HLA‐DRB1*11, HLA‐DRB1*15, HLA‐DQB1*03 and HLA‐DQB1*06 (assuming either allelic or dominant genetic model). We conclude that alleles of HLA‐A, ‐B, ‐C, ‐DRB1 and ‐DQB1 loci may represent potential biomarkers of COVID‐19 severity and/or mortality, which needs to be confirmed in a larger set of studies.

The humoral and cellular response tomRNA SARS‐CoV‐2 vaccine is influenced byHLApolymorphisms

“…The association between HLA alleles and vaccine response, as well as between HLA and COVID, varies among the different populations in relation to the frequency of the different alleles involved. If the association studies between HLA and vaccination response are limited in number, there are numerous studies that have analyzed the association between HLA and infection with SARS‐CoV‐2, comparing the HLA frequencies in infected versus the controls without infection (reviewed in References 13 and 52) or between HLA and COVID‐19 severity, comparing HLA frequencies in subgroups of patients with different clinical manifestations of the disease (reviewed in References 14 and 53).…”

“…A further element is that HLA class I molecules can be the ligands of KIR receptors of NK cells and can potentially influence the outcome of the infection and the progression of the disease by modulating NK activity 54 . In fact, although there are now hundreds of published studies looking at the association between HLA and COVID‐19, no firm conclusion can be drawn because of the heterogeneity in study designs, HLA typing methods, different geographical origin, and so forth (reviewed in References 9, 12, 14, and 53). There is practically no HLA allele that is not associated with COVID‐19 in at least a single study, and it is therefore misleading trying to find confirmation of the associations found in this study with those derived from HLA and COVID‐19 association studies.…”

The binding profile of SARS‐CoV‐2 with human leukocyte antigen polymorphisms reveals critical alleles involved in immune evasion

“…Details are shown in Supporting Information: Table . In addition, Dobrijević et al also identified HLA mutations associated with COVID‐19 susceptibility and severity by performing a meta‐analysis 50 . These studies highlight that HLA polymorphisms could affect viral peptide presentation and influence immunological protection.…”

A review of ancestrality and admixture in Latin America and the caribbean focusing on native American and African descendant populations

“…In this case, 29 haplotypes (41.4%) were ranked as African, 27 (38.6%) as European, and 14 (20.0%) ( Nunes et al, 2016 ). These HLA genes are associated with several infectious diseases, including malaria ( Hill et al, 1991 ) and COVID-19 ( Dobrijević et al, 2022 ). In some Quilombolas of Northwest and North Brazil, we have a possible repository of Amerindian alleles, checked by informative ancestral markers with Quilombolas and other African-Brazilian populations, with over 40% Amerindian ancestry contributing to the admixture of Brazilian populations ( Gontijo et al, 2014 ).…”