Malaspina Patrizia, Jodice Carla, Ciminelli Bianca Maria, Biancolella Michela, Colona Vito Luigi, Latini Andrea, Leonardis Francesca, Rogliani Paola, Novelli Antonio, Novelli Giuseppe, Novelletto Andrea
Department of Biology, Tor Vergata University of Rome, Via della Ricerca Scientifica 1, 00133, Rome, Italy.
Research Unit of Neurorehabilitation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Hum Genomics. 2025 Jan 30;19(1):7. doi: 10.1186/s40246-025-00719-8.
The Immunoglobulin Heavy Chain (IGH) genomic region is responsible for the production of circulating antibodies and warrants careful investigation for its association with COVID-19 characteristics. Multiple allelic variants within and across different IGH gene segments form a limited set of haplotypes. Previous studies have shown associations between some of these haplotypes and clinical outcomes of COVID-19. We typed 445 individuals of European ancestry, stratified for gender, age, and clinical status for 4 SNPs, two of which result in amino acid substitutions in IGHA2 and IGHG4, respectively. We analyzed associations at the single-locus level and for 4-loci haplotypes, inferred by phasing, after stratifying the overall cohort by gender, age, and disease severity.
Only weak evidence of significant differences between subgroups was obtained at the level of a single SNP. However, when the haplotypic data were analyzed for the young and old subgroups separately, uneven partitioning was observed regarding the occurrence of severe cases and Resistors. We then examined the cross-tabulation of disease severity in males and females, based on the presence of each haplotype in the genotype. Two haplotypes were underrepresented in young severe cases compared to old severe ones. The same two haplotypes were overrepresented among young Resistors. These findings provide stronger support for, the weak associations observed at the single locus level.
Two haplotypes seem to act as protective factors specifically in young individuals, counteracting the general increase in vulnerability with age. This observation aligns with stronger genetic effects seen in young patients for other susceptibility genes. Our findings complement previous research identifying specific genetic variants that influence COVID-19 susceptibility and severity, emphasizing the complex interplay between host genetics and viral infection outcomes. Our results are consistent with a potential causative role of IGH regulatory regions (e.g. HS1.2), which are flanked by the SNP set here analyzed.
免疫球蛋白重链（IGH）基因组区域负责循环抗体的产生，因其与新冠病毒疾病（COVID-19）特征的关联而值得仔细研究。不同IGH基因片段内和片段间的多个等位基因变体形成了一组有限的单倍型。先前的研究表明，其中一些单倍型与COVID-19的临床结果之间存在关联。我们对445名欧洲血统个体进行了基因分型，根据性别、年龄和临床状态对4个单核苷酸多态性（SNP）进行分层，其中两个SNP分别导致IGHA2和IGHG4中的氨基酸替换。在按性别、年龄和疾病严重程度对整个队列进行分层后，我们分析了单基因座水平以及通过定相推断的4基因座单倍型的关联。
在单个SNP水平上，仅获得了亚组间存在显著差异的微弱证据。然而，当分别对年轻和老年亚组的单倍型数据进行分析时，观察到重症病例和康复者的出现存在不均衡分布。然后，我们根据基因型中每种单倍型的存在情况，检查了男性和女性疾病严重程度的交叉表。与老年重症病例相比，两种单倍型在年轻重症病例中的比例较低。同样的两种单倍型在年轻康复者中的比例较高。这些发现为单基因座水平上观察到的微弱关联提供了更强的支持。
两种单倍型似乎特别在年轻人中起到保护作用，抵消了随着年龄增长易感性普遍增加的情况。这一观察结果与年轻患者中其他易感基因更强的遗传效应一致。我们的发现补充了先前的研究，这些研究确定了影响COVID-19易感性和严重程度的特定基因变体，强调了宿主遗传学与病毒感染结果之间复杂的相互作用。我们的结果与IGH调控区域（如HS1.2）的潜在致病作用一致，该区域位于此处分析的SNP集两侧。
