The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) has an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome events (CME) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (CME and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, CME and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people.

中文翻译：

---

男性克隆染色体嵌合体和 Y 染色体缺失是老年人 SARS-CoV-2 易感性的危险因素

由严重急性呼吸系统综合症冠状病毒 2（SARS-CoV-2，COVID-19）引起的持续大流行估计总体病死率为 1.38%（接种前），男性高出 53%，并且随着年龄的增长呈指数增长。在 SCOURGE 研究中诊断为 COVID-19 的 9578 人中，我们发现 133 例 (1.42%) 可检测到染色体事件 (CME) 的克隆嵌合体，226 例男性 (5.08%) 具有获得性 Y 染色体缺失 (LOY)。具有克隆马赛克事件（CME 和/或 LOY）的个体表现出 COVID-19 致死风险增加了 54%。LOY 与免疫功能障碍、促凝血活性和心血管风险的转录组生物标志物相关。参与对 SARS-CoV-2 的初始免疫反应的干扰素诱导基因也在 LOY 中下调。因此，CME 和 LOY 至少是老年患者 COVID-19 的性别偏见严重性和死亡率的一部分。鉴于其潜在的治疗和预后相关性，克隆嵌合体的评估应作为老年人 COVID-19 严重程度的生物标志物实施。