Center for Theragnosis, Biomedical Research Division, Korea Institute of Science and Technology, Seoul, Republic of Korea.
Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
PLoS One. 2021 Oct 28;16(10):e0259265. doi: 10.1371/journal.pone.0259265. eCollection 2021.
We sought to identify plasma biomarkers associated with spontaneous preterm birth (SPTB, delivery within 21 days of sampling) in women with preterm labor (PTL) without intra-amniotic infection/inflammation (IAI) using label-free quantitative proteomic analysis, as well as to elucidate specific protein pathways involved in these cases.
This was a retrospective cohort study comprising 104 singleton pregnant women with PTL (24-32 weeks) who underwent amniocentesis and demonstrated no evidence of IAI. Analysis of pooled plasma samples collected from SPTB cases and term birth (TB) controls (n = 10 for each group) was performed using label-free quantitative mass spectrometry for proteome profiling in a nested case-control study design. Eight candidate proteins of interest were validated by ELISA-based assay and a clot-based assay in the total cohort.
Ninety-one proteins were differentially expressed (P < 0.05) in plasma samples obtained from SPTB cases, of which 53 (58.2%) were upregulated and 38 (41.8%) were downregulated when compared to TD controls. A validation study confirmed that plasma from women who delivered spontaneously within 21 days of sampling contained significantly higher levels of coagulation factor Ⅴ and lower levels of S100 calcium binding protein A9 (S100A9), especially the former which was independent of baseline variables. The top-ranked pathways related to the 91 differentially expressed proteins were liver-X-receptor/retinoid X receptor (RXR) activation, acute phase response signaling, farnesoid X receptor/RXR activation, coagulation system, and complement system.
Proteomic analyses in this study identified potential novel biomarkers (i.e., coagulation factor V and S100A9) and potential protein pathways in plasma associated with SPTB in the absence of IAI in women with PTL. The present findings provide novel insights into the molecular pathogenesis and therapeutic targets specific for idiopathic SPTB.
本研究旨在采用无标记定量蛋白质组学分析，鉴定无羊膜内感染/炎症（IAI）的早产临产（PTL）孕妇中与自发性早产（SPTB，分娩发生在采样后 21 天内）相关的血浆生物标志物，并阐明这些病例中涉及的特定蛋白质途径。
这是一项回顾性队列研究，纳入了 104 例 PTL（24-32 周）孕妇，这些孕妇接受了羊膜穿刺术，且无 IAI 证据。采用无标记定量质谱法对来自 SPTB 病例和足月分娩（TB）对照者（每组 10 例）的合并血浆样本进行分析，以嵌套病例对照研究设计进行蛋白质组谱分析。在总队列中，通过 ELISA 检测和基于凝块的检测验证了 8 种候选感兴趣蛋白。
SPTB 病例组血浆样本中差异表达的蛋白有 91 种（P < 0.05），其中上调蛋白 53 种（58.2%），下调蛋白 38 种（41.8%）。验证研究证实，在采样后 21 天内自然分娩的女性血浆中，凝血因子Ⅴ水平显著升高，S100 钙结合蛋白 A9（S100A9）水平显著降低，尤其是前者独立于基线变量。与 91 个差异表达蛋白相关的排名最高的途径是肝 X 受体/视黄醇 X 受体（RXR）激活、急性期反应信号、法尼醇 X 受体/RXR 激活、凝血系统和补体系统。
本研究的蛋白质组学分析鉴定了潜在的新型生物标志物（即凝血因子 V 和 S100A9）和 PTL 孕妇无 IAI 的 SPTB 相关的潜在血浆蛋白途径。本研究结果为特发性 SPTB 的分子发病机制和治疗靶点提供了新的见解。
