BCNatal | Fetal Medicine Research Center (Hospital Clínic and Hospital Sant Joan de Déu), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Nephrology and Renal Transplantation Department, Hospital Clínic, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), University of Barcelona, Barcelona, Spain.
Sci Rep. 2021 Feb 4;11(1):3048. doi: 10.1038/s41598-021-82733-z.
Preeclampsia is a pregnancy-specific multisystem disorder and a leading cause of maternal and perinatal morbidity and mortality. The exact pathogenesis of this multifactorial disease remains poorly defined. We applied proteomics analysis on maternal blood samples collected from 14 singleton pregnancies with early-onset severe preeclampsia and 6 uncomplicated pregnancies to investigate the pathophysiological pathways involved in this specific subgroup of preeclampsia. Maternal blood was drawn at diagnosis for cases and at matched gestational age for controls. LC-MS/MS proteomics analysis was conducted, and data were analyzed by multivariate and univariate statistical approaches with the identification of differential pathways by exploring the global human protein-protein interaction network. The unsupervised multivariate analysis (the principal component analysis) showed a clear difference between preeclamptic and uncomplicated pregnancies. The supervised multivariate analysis using orthogonal partial least square discriminant analysis resulted in a model with goodness of fit (RX = 0.99, p < 0.001) and a strong predictive ability (QY = 0.8, p < 0.001). By univariate analysis, we found 17 proteins statistically different after 5% FDR correction (q-value < 0.05). Pathway enrichment analysis revealed 5 significantly enriched pathways whereby the activation of the complement and coagulation cascades was on top (p = 3.17e-07). To validate these results, we assessed the deposits of C5b-9 complement complex and on endothelial cells that were exposed to activated plasma from an independent set of 4 cases of early-onset severe preeclampsia and 4 uncomplicated pregnancies. C5b-9 and Von Willbrand factor deposits were significantly higher in early-onset severe preeclampsia. Future studies are warranted to investigate potential therapeutic targets for early-onset severe preeclampsia within the complement and coagulation pathway.
子痫前期是一种妊娠特有的多系统疾病，也是孕产妇和围产儿发病率和死亡率的主要原因。这种多因素疾病的确切发病机制仍不清楚。我们应用蛋白质组学分析方法对 14 例早发型重度子痫前期和 6 例无并发症妊娠的孕妇血液样本进行分析，以探讨涉及这种特定子痫前期亚组的病理生理途径。病例组在诊断时采集母血，对照组在匹配的孕龄时采集母血。进行 LC-MS/MS 蛋白质组学分析，通过探索全局人类蛋白质-蛋白质相互作用网络来识别差异途径，采用多变量和单变量统计方法对数据进行分析。非监督多元分析（主成分分析）显示子痫前期和无并发症妊娠之间存在明显差异。使用正交偏最小二乘判别分析的监督多元分析得出一个拟合度良好的模型（RX = 0.99，p < 0.001），并且具有很强的预测能力（QY = 0.8，p < 0.001）。通过单变量分析，我们在经过 5% FDR 校正（q 值 < 0.05）后发现 17 个蛋白统计学上存在差异。通路富集分析显示，有 5 个显著富集的通路，其中补体和凝血级联的激活位居首位（p = 3.17e-07）。为了验证这些结果，我们评估了来自 4 例早发型重度子痫前期和 4 例无并发症妊娠的独立样本的激活血浆对内皮细胞上 C5b-9 补体复合物沉积的影响。早发型重度子痫前期患者的 C5b-9 和血管性血友病因子沉积明显更高。有必要进行进一步的研究以探讨补体和凝血途径中针对早发型重度子痫前期的潜在治疗靶点。
