Unsupervised Placental Gene Expression Profiling Identifies Clinically Relevant Subclasses of Human Preeclampsia

Abstract

P reeclampsia (PE) is a potentially life-threatening, systemic, hypertensive disorder affecting 3% to 5% of all pregnancies. Responsible for >60 000 maternal deaths each year, 1 PE is also a leading cause of fetal/neonatal mortality and morbidity. Classically, PE has been defined as new-onset hypertension and proteinuria after 20 weeks of gestation. However, the clinical presentation of PE is highly variable among women, and diagnostic guidelines now include signs and symptoms that are reflective of disease in ≥1 organ systems (liver, kidney, blood, and brain 2,3 ). Apart from expectant management and delivery of the infant and the placenta, there currently exists no cure or effective treatments for PE.The placenta is widely considered to be the central component of the PE disease process, and as it is not required after birth, this presents a unique opportunity to assess a clinically relevant tissue involved in a hypertensive pathology. Accordingly, numerous placental analyses have been conducted with the aim of identifying early detection markers or candidates for therapeutic intervention in PE. These studies have uncovered involvement of molecular pathways, such as oxidative stress and secretion, [4][5][6] and many secreted factors with disrupted expression during PE have been investigated as candidate blood biomarkers of this pathology. [7][8][9][10] However, the predictive power of these molecules demonstrate low sensitivity at clinically relevant false-positive rates 7 and, therefore, are not presently recommended for use as screening tools for PE. 11 We, [12][13][14] and others, 15,16 have proposed that this lack of robust biomarkers and effective treatments for PE is because of the multifactorial nature of this disease, a notion supported by considerable evidence within the human literature. [17][18][19][20][21] Further support also exists in the numerous developed animal models of PE that recapitulate many of the human symptoms and pathologies because these are the result of a range of initial insults, involving disruptions in placental 22,23 or maternal 24 genes, or a predisposing baseline maternal hypertension. 25 As such, past placental microarray, and even meta-analysis, 26,27 studies with small and highly selected patient cohorts, predominately assessed using a binary classification system (of PE versus control), do not accurately reflect the true clinical presentation of patients. Even the separation of women into earlyonset (diagnosis before 34 weeks) and late-onset PE groups 18,21 Abstract-Preeclampsia (PE) is a complex, hypertensive disorder of pregnancy, demonstrating considerable variability in maternal symptoms and fetal outcomes. Unfortunately, prior research has not accounted for this variability, resulting in a lack of robust biomarkers and effective treatments for PE. Here, we created a large (N=330) clinically relevant human placental microarray data set, consisting of 7 previously published studies and 157 highly annotated new samples from a single BioBank. Applying unsupervise...

Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction

“…Leavey et al 39 found specific correlations with microarray data (from large cohorts of preeclamptic placentas) with clinical findings and propose subclasses of preeclampsia distinct to the canonical disease (which is driven by antiangiogenic factors). They identified a cluster of patients they coined immunologic preeclampsia where the main drivers of the disease may be immunologic.…”

“…They identified a cluster of patients they coined immunologic preeclampsia where the main drivers of the disease may be immunologic. 39 It is therefore possible that PPIs might be less effective for subtypes of preeclampsia where antiangiogenic factors play less of a role. As the field of preeclampsia subtyping matures, it may be feasible to stratify response to PPIs treatment in future clinical trials with preeclampsia subtyping.…”

Low Molecular Weight Heparin Improves Endothelial Function in Pregnant Women at High Risk of Preeclampsia

“…It is also important to note that, although preeclampsia can be predicted with reasonable accuracy, it is a heterogeneous disease, and the relative contributions of risk factors are not known. 35 Additionally, the effects of LMWH on maternal cardiovascular was assessed for an acute time period after one administration of the agent; further longitudinal studies are thus warranted to evaluate whether the acute treatment effects demonstrated are maintained for a longer period of time.…”

Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations

“…10 In addition to morphologic and targeted molecular analyses, investigators are also applying global transcriptional profiling approaches to better understand the placental defects that are associated with preeclampsia. To date, these studies have focused on chorionic villi, 11,12 the maternal-fetal interface, 13 or purified cytotrophoblasts as they differentiate along the invasive pathway in vitro. 14 These studies have the advantage of being unbiased therefore enabling the de novo discovery of misregulated genes.…”