[论文解读] Sex Differences in Severity and Mortality Among Patients With COVID-19: Evidence from Pooled Literature Analysis and Insights from Integrated Bioinformatic Analysis

Xiyi Wei, Yu‐Tian Xiao+13 more|arXiv (Cornell University)|Mar 30, 2020

COVID-19 Clinical Research Studies参考文献 82被引用 69

一句话总结

本研究对COVID-19患者进行荟萃分析，显示男性的病情严重程度和死亡率更高，并结合生物信息学数据，提示雄激素受体调控ACE2可能是性别差异的潜在机制。

ABSTRACT

Objective: To conduct a meta-analysis of current studies that examined sex differences in severity and mortality in patients with COVID-19, and identify potential mechanisms underpinning these differences. Methods: We performed a systematic review to collate data from observational studies examining associations of sex differences with clinical outcomes of COVID-19. PubMed, Web of Science and four preprint servers were searched for relevant studies. Data were extracted and analyzed using meta-analysis where possible, with summary data presented otherwise. Publicly available bulk RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), and chromatin immunoprecipitation sequencing (ChIP-seq) data were analyzed to explore the potential mechanisms underlying the observed association. Results: 39 studies met inclusion criteria, representing 77932 patients, of which 41510 (53.3%) were males. Men were at a markedly increased risk of developing severe cases compared with women. Furthermore, the pooled odds ratio (OR) of mortality for male group compared with the female group indicated significant higher mortality rate for male. Data from scRNA-seq suggest that men have a higher amount of ACE2-expressing pulmonary alveolar type II cells than women. Sex-based immunological differences exist. The expression of androgen receptor (AR) is positively correlated with ACE2, and there is evidence that AR may directly regulate the expression of ACE2. Conclusions: This meta-analysis detected an increased severity and mortality rate in the male populations with COVID-19, which might be attributable to the sex-based differences in cellular compositions and immunological microenvironments of the lung. The host cell receptor ACE2 is likely regulated by AR signaling pathway, which is identified as a potential target for prevention and treatment of SARS-Cov-2 infections in men.

研究动机与目标

• 评估跨观察性研究中COVID-19的性别差异是否存在于严重程度和死亡率。
• 量化男性与女性患者之间风险差异的大小。
• 利用生物信息学分析提出潜在的生物学机制来解释观察到的性别差异。

提出的方法

• 系统性检索PubMed、Web of Science以及四个预印本服务器，以获取关于性别与COVID-19结局的观察性研究。
• 在可行的情况下进行数据提取和荟萃分析；否则进行描述性综合。
• 分析公开的bulk RNA-seq、scRNA-seq和ChIP-seq数据集，以探索与ACE2表达和性激素相关的机制。
• 相关性分析以将雄激素受体信号传导与ACE2表达联系起来。

实验结果

研究问题

• RQ1 男性患者相较于女性患者是否存在更高的严重COVID-19风险？
• RQ2 在COVID-19患者中，男性的死亡率是否高于女性？
• RQ3 哪些生物学机制（如ACE2表达模式、AR signaling）可能解释观察到的性别差异？

主要发现

• 男性相比女性在发展为重症COVID-19方面存在显著增加的风险。
• 死亡率的合并比值比在男性中显著高于女性。
• scRNA-seq数据提示男性肺泡Ⅱ型细胞中ACE2表达量高于女性。
• 观察到基于性别的免疫学差异，且AR信号传导与ACE2表达呈正相关。
• AR可能直接调控ACE2表达，提示雄激素通路可能成为预防和治疗的潜在靶点。