Romero Roberto, Erez Offer, Maymon Eli, Chaemsaithong Piya, Xu Zhonghui, Pacora Percy, Chaiworapongsa Tinnakorn, Done Bogdan, Hassan Sonia S, Tarca Adi L
Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI; Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI.
Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI.
Am J Obstet Gynecol. 2017 Jul;217(1):67.e1-67.e21. doi: 10.1016/j.ajog.2017.02.037. Epub 2017 Mar 3.
Pregnancy is accompanied by dramatic physiological changes in maternal plasma proteins. Characterization of the maternal plasma proteome in normal pregnancy is an essential step for understanding changes to predict pregnancy outcome. The objective of this study was to describe maternal plasma proteins that change in abundance with advancing gestational age and determine biological processes that are perturbed in normal pregnancy.
A longitudinal study included 43 normal pregnancies that had a term delivery of an infant who was appropriate for gestational age without maternal or neonatal complications. For each pregnancy, 3 to 6 maternal plasma samples (median, 5) were profiled to measure the abundance of 1125 proteins using multiplex assays. Linear mixed-effects models with polynomial splines were used to model protein abundance as a function of gestational age, and the significance of the association was inferred via likelihood ratio tests. Proteins considered to be significantly changed were defined as having the following: (1) >1.5-fold change between 8 and 40 weeks of gestation; and (2) a false discovery rate-adjusted value of P < .1. Gene ontology enrichment analysis was used to identify biological processes overrepresented among the proteins that changed with advancing gestation.
The following results were found: (1) Ten percent (112 of 1125) of the profiled proteins changed in abundance as a function of gestational age; (2) of the 1125 proteins analyzed, glypican-3, sialic acid-binding immunoglobulin-type lectin-6, placental growth factor, C-C motif-28, carbonic anhydrase 6, prolactin, interleukin-1 receptor 4, dual-specificity mitogen-activated protein kinase 4, and pregnancy-associated plasma protein-A had more than a 5-fold change in abundance across gestation (these 9 proteins are known to be involved in a wide range of both physiological and pathological processes, such as growth regulation, embryogenesis, angiogenesis immunoregulation, inflammation etc); and (3) biological processes associated with protein changes in normal pregnancy included defense response, defense response to bacteria, proteolysis, and leukocyte migration (false discovery rate, 10%).
The plasma proteome of normal pregnancy demonstrates dramatic changes in both the magnitude of changes and the fraction of the proteins involved. Such information is important to understand the physiology of pregnancy and the development of biomarkers to differentiate normal vs abnormal pregnancy and determine the response to interventions.
妊娠伴随着母体血浆蛋白的显著生理变化。对正常妊娠母体血浆蛋白质组进行表征是理解变化以预测妊娠结局的重要一步。本研究的目的是描述随着孕周增加丰度发生变化的母体血浆蛋白，并确定正常妊娠中受到干扰的生物学过程。
一项纵向研究纳入了43例正常妊娠，这些妊娠足月分娩出适于胎龄的婴儿，且无母体或新生儿并发症。对于每例妊娠，采集3至6份母体血浆样本（中位数为5份），使用多重检测法测定1125种蛋白质的丰度。采用带有多项式样条的线性混合效应模型将蛋白质丰度建模为孕周的函数，并通过似然比检验推断关联的显著性。被认为有显著变化的蛋白质定义为具备以下条件：(1) 在妊娠8至40周之间变化超过1.5倍；(2) 经错误发现率调整后的P值 < 0.1。基因本体富集分析用于识别随着孕周增加而变化的蛋白质中过度富集的生物学过程。
发现以下结果：(1) 所分析的蛋白质中有10%（1125种中的112种）丰度随孕周变化；(2) 在分析的1125种蛋白质中，磷脂酰肌醇蛋白聚糖-3、唾液酸结合免疫球蛋白样凝集素-6、胎盘生长因子、C-C基序趋化因子28、碳酸酐酶6、催乳素、白细胞介素-1受体4、双特异性丝裂原活化蛋白激酶4和妊娠相关血浆蛋白-A在整个妊娠期丰度变化超过5倍（已知这9种蛋白质参与广泛的生理和病理过程，如生长调节、胚胎发生、血管生成、免疫调节、炎症等）；(3) 与正常妊娠中蛋白质变化相关的生物学过程包括防御反应、对细菌的防御反应、蛋白水解和白细胞迁移（错误发现率为10%）。
正常妊娠的血浆蛋白质组在变化幅度和涉及的蛋白质比例方面均表现出显著变化。此类信息对于理解妊娠生理学以及开发区分正常与异常妊娠并确定对干预措施反应的生物标志物非常重要。
