Spartano Serena, Faggiano Maria Vittoria, Guidi Giovanna, D'Ambrosio Pino, Vaisfeld Alessandro, Novelli Agnese, Falqui Salvatore, Cingolani Antonella, Lambertenghi Lorenza, Visentin Alessandro, Azzini Annamaria, Righi Elda, Trecarichi Enrico Maria, Mazzitelli Maria, Coletti Silvano, Mous Jan, Rademacher Thomas W, Torti Carlo, Tacconelli Evelina, Fantoni Massimo, Cauda Roberto, Tiziano Francesco Danilo
Section of Genomic Medicine, Department of Life Sciences and Public Health, Catholic University of Sacred Heart, 00168 Rome, Italy.
Complex Unit of Medical Genetics, Department of Laboratory and Infectivologic Sciences, Policlinico "A. Gemelli" Foundation, 00168 Rome, Italy.
Int J Mol Sci. 2024 Dec 8;25(23):13198. doi: 10.3390/ijms252313198.
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 , , , , , and 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.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染是2019冠状病毒病（COVID-19）的病原体，其临床表现多样，从无症状感染到严重的肺功能障碍甚至死亡。COVID-19严重程度的差异在很大程度上归因于宿主的遗传特征，提示其具有多基因遗传结构，但尚无明显有力证据表明存在与性别相关的遗传差异。在这项意大利的回顾性病例对照研究中，我们通过下一代测序（NGS）分析，研究了COVID-19严重程度（重症患者与无症状/轻症已康复个体）与HLA基因变异之间的关联。我们在HLA的A、B、C、DRB1、DQB1和DPA1基因中鉴定出了与COVID-19严重程度相关的显著HLA等位基因（按照传统命名法）、单核苷酸多态性（SNP）和单倍型。有趣的是，这些变异显示出与生物学性别相关的效应。此外，我们还鉴定出了与COVID-19严重程度相关的特定单倍型，这些单倍型由不同的传统HLA等位基因共享，在此称为“超级单倍型”。与传统HLA等位基因相比，这些单倍型对疾病严重程度具有生物学性别特异性影响，并显著增加了重症COVID-19的风险（优势比高达15）。我们的数据表明，修订当前的HLA命名法可能有助于识别对疾病易感性影响更强的变异，并且关联研究可能会因按生物学性别对患者进行分层而受益。如果这些发现在其他疾病模型中得到验证，它们可能有助于基于HLA系统定义两性免疫反应中的功能多样性。最后，鉴于全球大流行的死亡率，我们在此假设SARS-CoV-2可能充当了自然选择的触发因素，导致普通人群中HLA等位基因频率发生漂移。
