A Cross-Sectional Analysis of Syncytiotrophoblast Membrane Extracellular Vesicles Derived Transcriptomic Biomarkers in Preeclampsia

Background Preeclampsia (PE) is a pregnancy-specific hypertensive disorder affecting 2-8% of pregnancies worldwide. Biomarker(s) for PE exists, but while these have excellent negative predictive value, their positive predictive value is poor. Extracellular vesicles released by the placenta into the maternal circulation, syncytiotrophoblast membrane extracellular vesicles - STB-EVs-have been identified as being involved in PE with the potential to act as liquid biopsies. Objective To identify differences in STB-EV and placenta transcriptome between PE and normal pregnancy (NP). Methods We performed RNA-sequencing (RNA-seq) on placental tissue, medium/large and small STB-EVs from PE (n=6) and NP (n=6), followed by bioinformatic analysis to identify targets that could be used in the future for EV-based diagnostic tests for preeclampsia. Some of the identified biomarkers were validated with real-time polymerase chain reactions. Results Our analysis identified and verified the differential expression of FLNB, COL17A1, SLC45A4, LEP, HTRA4, PAPP-A2, EBI3, HSD17B1, FSTL3, INHBA, SIGLEC6, and CGB3. Our analysis also identified interesting mechanistic processes via an in-silico prediction of STB-EV-based mechanistic pathways. Conclusions In this study, we identified potential biomarkers and mechanistic gene pathways that may be important in the pathophysiology of PE and could be further explored in future studies. Funding This research was funded by the Medical Research Council (MRC Programme Grant (MR/J0033601) and the Medical & Life Sciences translational fund (BRR00142 HE01.01) ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was funded by the Medical Research Council (MRC Programme Grant (MR/J0033601) and the Medical & Life Sciences translational fund (BRR00142 HE01.01) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This ethical approval for this research was granted by the Central Oxfordshire Research Ethics Committee C (REFS 07/H0607/74 & 07/H0606/148). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at DOI: 10.17632/6s5fkd3z7t.1