Using proteomics to advance the search for potential biomarkers for preeclampsia: A systematic review and meta-analysis
April
Using proteomics to advance the search for potential biomarkers for preeclampsia: A systematic review and meta-analysis
Thy Pham Hoai NguyenID 0 1
Cameron James Patrick 1
Laura Jean Parry 0 1
Mary Familari 0 1
0 School of BioSciences, University of Melbourne , Parkville , Australia , 2 Statistical Consulting Centre, University of Melbourne , Parkville , Australia
1 Editor: Cassandra Nichole Spracklen, University of North Carolina at Chapel Hill , UNITED STATES
Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity and mortality worldwide. Although predictive multiparametric screening is being developed, it is not applicable to nulliparous women, and is not applied to low-risk women. As PE is considered a heterogenous disorder, it is unlikely that any single multiparametric screening protocol containing a small group of biomarkers could have the required accuracy to predict all PE subgroups. Given the etiology of PE is complex and not fully understood, it begs the question, whether the search for biomarkers based on the predominant view of impaired placentation involving factors predominately implicated in angiogenesis and inflammation, has been too limiting. Here we highlight the enormous potential of state-of-the-art, high-throughput proteomics, to provide a comprehensive and unbiased approach to biomarker identification. Our literature search identified 1336 articles; after review, 45 studies with proteomic data from PE women that were eligible for inclusion. From 710 proteins with altered abundance, we identified 13 common circulating proteins, some of which had not been previously considered as prospective biomarkers of PE. An additional search of the literature for original publications testing any of the 13 common proteins using non-proteomic techniques was also undertaken. Strikingly, 9 of these common proteins had been independently evaluated in PE studies as potential biomarkers.
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Data Availability Statement: All relevant data are
within the manuscript and its Supporting
Information files.
Funding: The author(s) received no specific
funding for this work.
Competing interests: The authors have declared
that no competing interests exist.
Abbreviations: EOPE, Early onset preeclampsia;
FGR, fetal growth restriction; LOPE, late onset
preeclampsia; NP, normal pregnant; PAPP-A,
Background
Methods and findings
Conclusion
This study highlights the potential of using high-throughput data sets, which are
comprehensive and without bias, to identify a profile of proteins that may improve predictions of PE and
understanding of its etiology. We bring to the attention of the medical and research
communities that the strengths and advantages of using data from high-throughput studies for
biomarker discovery would be increased dramatically, if first and second trimester samples
pregnancy-associated plasma protein-A; PE,
preeclampsia; PlGF, placental growth factor; sEng,
soluble endoglin; sFlt-1, soluble fms-like tyrosine
kinase-1; VEGF, vascular endothelial growth factor.
were collected for proteomics, and if standardized guidelines for patient reporting and data
collection were implemented.
Introduction
Preeclampsia (PE), described as a syndrome that affects 5?10% of all pregnancies, remains a
leading cause of maternal and perinatal morbidity and mortality [
1?3
]. Although rare, PE can
develop into eclampsia, which is responsible for over 50,000 maternal deaths globally per year
[
4
]. Furthermore, PE is known to affect both the mother and child well beyond pregnancy and
can lead to a higher risk of subsequent cardiovascular diseases later in life [
5
]. Currently, the
American College of Obstetricians and Gynecologists (ACOG) [
6
], the International Society
for the Study of Hypertension in Pregnancy [7] and the Society of Obstetric Medicine of
Australia and New Zealand (SOMANZ) [8] characterize PE by the presence of new onset
hypertension ( 140/90 mm Hg) after 20 weeks of gestation, accompanied by at least one end organ
dysfunction (e.g. kidney, liver) or fetal growth restriction (FGR). This updated criterion
reflects the growing awareness of the heterogeneity of the etiology of PE.
Clinicians predominantly rely on PE risk factors including age (>35 years), previous PE or
family history, multiple gestation, BMI (>25 kg/m2), ethnicity, and whether assisted
reproductive techniques were involved, leading to classification of low or high risk [9]. However, clinical
assessment of these risk factors has limited predictive ability [10,11] because it is not applicable
to nulliparous women, and does not encompass all women who develop PE, particularly low
risk women who are not monitored as frequently. This is underscored by a recent retrospective
study in which 3,230 women, of those classified as low risk pregnancies (28.7% of 10 million
women), unexpectedly developed eclampsia [12]. Thus, accurate screening for PE early in
pregnancy remains a significant challenge.
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