Sex-specific HLA alleles contribute to the modulation of COVID-19 severity

Article


Spartano, S., Faggiano, M.V., Guidi, G., D’Ambrosio, P., Vaisfeld, A., Novelli, A., Falqui, S., Cingolani, A., Lambertenghi, L., Visentin, A., Azzini, A., Righi, E., Trecarichi, E., Mazzitelli, M., Coletti, S., Mous, J., Rademacher, T.W., Torti, C., Tacconelli, E., Fantoni, M., Cauda, R. and Tiziano, F. 2024. Sex-specific HLA alleles contribute to the modulation of COVID-19 severity. International Journal of Molecular Sciences. 25 (23). https://doi.org/10.3390/ijms252313198
TypeArticle
TitleSex-specific HLA alleles contribute to the modulation of COVID-19 severity
AuthorsSpartano, S., Faggiano, M.V., Guidi, G., D’Ambrosio, P., Vaisfeld, A., Novelli, A., Falqui, S., Cingolani, A., Lambertenghi, L., Visentin, A., Azzini, A., Righi, E., Trecarichi, E., Mazzitelli, M., Coletti, S., Mous, J., Rademacher, T.W., Torti, C., Tacconelli, E., Fantoni, M., Cauda, R. and Tiziano, F.
Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, responsible for Coronavirus Disease 2019 (COVID-19), exhibits a spectrum of clinical manifestations, ranging from asymptomatic to severe pulmonary dysfunction or death. The variability in COVID-19 severity has largely been attributed to the host’s genetic characteristics, suggesting a polygenic genetic architecture, without significant strong evidence of sex-related genetic differences. In this Italian retrospective case–control study, we investigated the association between COVID-19 severity (severe vs. asymptomatic/oligosymptomatic healed individuals) and HLA gene variants, analyzed by next-generation sequencing (NGS). We identified significant HLA alleles (according to the conventional nomenclature), SNPs and haplotypes in the HLA-B, -C, -F, -DQA1, -DRB1, and -DRB5 genes associated with COVID-19 severity. Interestingly, these variants showed biological sex-related effects. Also, we identified specific haplotypes associated with COVID-19 severity that are shared by different conventional HLA alleles, indicated here as “super-haplotypes”. These haplotypes had a biological sex-specific impact on disease severity and markedly increased the risk of severe COVID-19 compared to the conventional HLA alleles (odds ratio of up to 15). Our data suggest that the revision of the current HLA nomenclature may help to identify variants with a stronger effect on disease susceptibility and that association studies could benefit from the stratification of patients by biological sex. If replicated in other disease models, these findings could help to define the functional diversity in immune response between sexes, also based on the HLA system. Finally, due to the global pandemic’s mortality rate, we hypothesize here that SARS-CoV-2 may have acted as a natural selection trigger, leading to a drift in HLA allelic frequencies in the general population.

Keywordsimmune system modulation; Italy - epidemiology; biological sex differences; HLA Antigens - genetics; Humans; Case-Control Studies; Retrospective Studies; HLA gene variants; Middle Aged; Haplotypes; Genetic Predisposition to Disease; Severity of Illness Index; Gene Frequency; Adult; Female; Aged; genetic architecture; Alleles; next-generation sequencing; genetic association study; Male; Polymorphism, Single Nucleotide; COVID-19 - genetics - immunology - virology; COVID-19; case–control study; SARS-CoV-2; Sex Factors
Sustainable Development Goals3 Good health and well-being
Middlesex University ThemeHealth & Wellbeing
PublisherMDPI
JournalInternational Journal of Molecular Sciences
ISSN
Electronic1422-0067
Publication dates
Online08 Dec 2024
Print08 Dec 2024
Publication process dates
Submitted26 Sep 2024
Accepted20 Nov 2024
Deposited20 Jan 2025
Output statusPublished
Publisher's version
License
File Access Level
Open
Digital Object Identifier (DOI)https://doi.org/10.3390/ijms252313198
PubMed ID39684907
PubMed Central IDPMC11642212
National Library of Medicine IDID101092791
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