Uncovering Novel and Effective Biomarkers for Preeclampsia

Preeclampsia affects up to 5% of pregnancies and leads to approximately 76,000 maternal deaths every year, as well as affecting fetal growth and development.^1-3 Although many questions remain unanswered, it’s thought that it could occur when the placenta does not anchor deeply in the uterine wall during the first trimester, resulting in abnormal vascular development and upsetting complex interactions at the fetal–maternal interface. This ultimately interferes with oxygen and nutrient delivery. The most severe form is known as early-onset preeclampsia (EOPE), which occurs before 34 weeks’ gestation. Despite new understanding around clinical manifestations, the underlying molecular mechanisms have not been fully explained.

New work published in the Journal of Proteome Research aims to change this by uncovering novel and effective biomarkers.⁴ This builds on older research that looked at serum proteins using mass spectrometry—the findings of which supported the theory that preeclampsia is a heterogeneous disorder that might be sub-classified by a defined proteome signature in maternal blood.⁵

In their search for biomarkers, the researchers performed a comparative analysis of 15 women with EOPE and 15 with normal pregnancies. Using tandem mass tag-based quantitative proteomics, they were able to identify differentially expressed proteins between the two groups, which were subsequently validated with parallel reaction monitoring. The analysis revealed 59 differentially expressed proteins, with 25 up-regulated and 34 down-regulated proteins in EOPE placental tissues compared to those from normal pregnancies. Validation confirmed differential expression of six key proteins that could be implicated in EOPE pathogenesis. This included elevated PAPPA2, which aligns with other reports in the literature.^6,7 Other upregulated proteins were SLC16A3 and ERO1A, while CALD1, KRT18, and DES were down-regulated. Gene ontology analysis suggested the most represented process among the differentially expressed proteins was biological regulation—predominantly binding functions—and the cellular component category was the most associated with protein-containing complexes. Of note, these proteins also highlighted the potential involvement of estrogen-signaling pathways and dilated cardiomyopathy.

Inflammation is also thought to be involved in the development of preeclampsia. Measurement of inflammation-related proteins has revealed 28 inflammation-related markers that differ between women with and without preeclampsia.⁸ The largest changes were seen for fibroblast growth factor-21 and cysteine–cysteine motif chemokine ligand-20 (CCL20). The authors note this is the first time that CCL20 has been found to be upregulated, and this could represent another novel potential predictive and diagnostic biomarker. These new papers suggest the knowledge around preeclampsia is growing, and it is hoped this will translate into better outcomes for both mothers and babies in the coming years.

References

1. Magee, L.A. et al. The 2021 International Society for the Study of Hypertension in Pregnancy classification, diagnosis & management recommendations for international practice. Pregnancy Hypertens 2022, 27, 148–169.
2. Chappell, L.C. et al. Pre-eclampsia. Lancet 2021, 398 (10297), 341–354.
3. Poon, L.C. et al. The International Federation of Gynecology and Obstetrics (FIGO) initiative on pre-eclampsia: A pragmatic guide for first-trimester screening and prevention. Int. J. Gynaecol Obstet 2019, 145 (Suppl 1), 1–33.
4. Pecks, U. et al. Multifactorial analysis of affinity-mass spectrometry data from serum protein samples: A strategy to distinguish patients with preeclampsia from matching control individuals. J Am Soc Mass Spectrom 2010, 21, 10, 1699–1711.
5. Zhou, J. et al. Proteomic Analysis Reveals Differential Protein Expression in Placental Tissues of Early-Onset Preeclampsia Patients. J. Proteome Res. 2024, 23, 10, 4433–4442.
6. Chen, X. et al. The potential role of pregnancy-associated plasma protein-A2 in angiogenesis and development of preeclampsia. Hypertens Res. 2019, 42 (7), 970–980.
7. Kramer, A.W. et al. Differential expression of human placental PAPP-A2 over gestation and in preeclampsia. Placenta 2016, 37, 19–25.
8. Wang X, et al. Plasma Olink Proteomics Identifies CCL20 as a Novel Predictive and Diagnostic Inflammatory Marker for Preeclampsia. J. Proteome Res. 2022, 21, 12, 2998–3006.