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. 2024 Dec 8;25(23):13198.
doi: 10.3390/ijms252313198.

Sex-Specific HLA Alleles Contribute to the Modulation of COVID-19 Severity

Serena Spartano  1   2 , Maria Vittoria Faggiano  1   2 , Giovanna Guidi  3   4 , Pino D'Ambrosio  1   2 , Alessandro Vaisfeld  1   2 , Agnese Novelli  1   2 , Salvatore Falqui  1   2 , Antonella Cingolani  3   4 , Lorenza Lambertenghi  5 , Alessandro Visentin  5 , Annamaria Azzini  5 , Elda Righi  5 , Enrico Maria Trecarichi  6 , Maria Mazzitelli  6 , Silvano Coletti  7 , Jan Mous  7 , Thomas W Rademacher  8 , Carlo Torti  3   4   6 , Evelina Tacconelli  5   9 , Massimo Fantoni  3   4 , Roberto Cauda  3   4 , Francesco Danilo Tiziano  1   2
Affiliations

Sex-Specific HLA Alleles Contribute to the Modulation of COVID-19 Severity

Serena Spartano et al. Int J Mol Sci. .

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.

Keywords: COVID-19; HLA gene variants; SARS-CoV-2; biological sex differences; case–control study; genetic architecture; genetic association study; immune system modulation; next-generation sequencing.

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Conflict of interest statement

Silvano Coletti and Jan Mous were employed by the company Chelonia SA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
(A): Size of the coding region of each gene (bp) vs. # of variants. (B): Ratio between # of variants and amount of sequenced gDNA.
See this image and copyright information in PMC

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