Journal Article

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

Righi, Elda, D’Ambrosio, Pino, Torti, Carlo, Spartano, Serena, Visentin, Alessandro, Azzini, Annamaria, Mous, Jan, Tacconelli, Evelina, Trecarichi, Enrico Maria, Cingolani, Antonella, Fantoni, Massimo, Guidi, Giovanna, Novelli, Agnese, Vaisfeld, Alessandro, Cauda, Roberto, Faggiano, Maria Vittoria, Falqui, Salvatore, Mazzitelli, Maria, Rademacher, Thomas W., Lambertenghi, Lorenza, Tiziano, Francesco Danilo, Coletti, Silvano

2024

Overview

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.

• Publisher: MDPI AG
• Subject: Adult / Aged / Alleles / Allelomorphism / Analysis / Asymptomatic / Case-Control Studies / Coronaviruses / COVID-19 / COVID-19 - genetics / COVID-19 - immunology / COVID-19 - virology / Dictionaries / Disease susceptibility / Female / Females / Gender differences / Gene Frequency / Genes / Genetic Predisposition to Disease / Haplotypes / Health aspects / Histocompatibility antigens / HLA Antigens - genetics / HLA histocompatibility antigens / Humans / Infections / Italy / Italy - epidemiology / Male / Males / Massachusetts / Medical research / Medicine, Experimental / Middle Aged / Mortality / Polymorphism, Single Nucleotide / Population / Retrospective Studies / SARS-CoV-2 / Severe acute respiratory syndrome / Severe acute respiratory syndrome coronavirus 2 / Severity of Illness Index / Sex Factors / Sexes / United States