Transcriptomic profile assessment for preeclampsia prediction and early diagnostics

Aim: to develop a model for predicting preeclampsia (PE) based on the clinically most significant differentially expressed plasma microRNAs.

Materials and Methods. A prospective observational comparative study was conducted with 62 women, divided into two parallel groups: 32 patients with PE and 30 clinically healthy women with uncomplicated pregnancy. Transcriptomic analysis was performed to identify differentially expressed blood plasma microRNAs using next generation sequencing (NGS).

Results. Calculation of risk ratios for PE development allowed to identify 14 plasma microRNAs that influence the development of PE pathology. PE-associated microRNAs hsa-miR-103a-3p, hsa-miR-451a and hsa-miR-516a-5p have a high diagnostic value when combined to assess their blood plasma expression level in early pregnancy stages.

Conclusion. The developed prognostic model can be applied to pregnant women at risk for PE development, which may further reduce obstetric complications and improve perinatal outcomes.

1. Scholien R.R., Hopman M.T., Sweep F.C. et al. Co-occurrence of cardiovascular and prothrombotic risk factors in women with a history of preeclampsia. Obstet Gynecol. 2013;121(1):97–105. https://doi.org/10.1097/aog.0b013e318273764b.

2. Belokrinitskaya T.E., Frolova N.I., Anokhova L.I. Molecular genetic predictors of pregnancy complications. [Molekulyarno-geneticheskie prediktory oslozhnenij beremennosti]. Novosibirsk: Nauka, 2019. 188 p. (In Russ.).

3. The global strategy for women’s, children’s and adolescents’ health (2016-2030). New York: United Nations, 2015. 108 p. Available at: https://www.who.int/docs/default-source/child-health/the-global-strategy-for-women-s-children-s-and-adolescents-health-2016-2030.pdf. [Accessed: 20.04.2024].

4. Mészáros B., Kukor Z., Valent S. Recent advances in the prevention and screening of preeclampsia. J Clin Med. 2023;12(18):6020. https://doi.org/10.3390/jcm12186020.

5. ACOG Practice Bulletin No. 202: Gestational Hypertension and Preeclampsia. Obstet Gynecol. 2019;133(1):1. https://doi.org/10.1097/AOG.0000000000003018.

6. Tiruneh S.A., Vu T.T.T., Moran L.J. et al. Externally validated prediction models for pre-eclampsia: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2024;63(5):592–604. https://doi.org/10.1002/uog.27490.

7. Danielli M., Thomas R.C., Gillies C.L. et al. Blood biomarkers to predict the onset of pre-eclampsia: a systematic review and meta-analysis. Heliyon. 2022;8(11):e11226. https://doi.org/10.1016/j.heliyon.2022.e11226.

8. Roberts J.M., Rich-Edwards J.W., McElrath T.F. et al; Global Pregnancy Collaboration. Subtypes of preeclampsia: recognition and determining clinical usefulness. Hypertension. 2021;77(5):1430–41. https://doi.org/10.1161/HYPERTENSIONAHA.120.14781.

9. Xie G., Chen H., He C. et al. The dysregulation of miRNAs in epilepsy and their regulatory role in inflammation and apoptosis. Funct Integr Genomics. 2023;23(3):287. https://doi.org/10.1007/s10142-023-01220-y.

10. Redman C.W.G., Staff A.C., Roberts J.M. Syncytiotrophoblast stress in preeclampsia: the convergence point for multiple pathways. Am J Obstet Gynecol. 2022;226(2S):S907–S927. https://doi.org/10.1016/j.ajog.2020.09.047.

11. Gareev I.F., Beylerli O.A. Circulating microRNAs as biomarkers: what are perspectives? [Cirkuliruyushchie mikroRNK kak biomarkery: kakie perspektivy?] Profilakticheskaya medicina. 2018;21(6):142–50. (In Russ.). https://doi.org/10.17116/profmed201821061142.

12. Clinical guidelines – Preeclampsia. Eclampsia. Edema, proteinuria and hypertensive disorders during pregnancy, childbirth and the postpartum period – 2021-2022-2023 (24.06.2021). [Klinicheskie rekomendacii – Preeklampsiya. Eklampsiya. Oteki, proteinuriya i gipertenzivnye rasstrojstva vo vremya beremennosti, v rodah i poslerodovom periode – 2021-2022-2023 (24.06.2021). Moscow: Ministerstvo zdravoohraneniya Rossiijskoj Federacii, 2021. 54 p. Available at: https://cr.minzdrav.gov.ru/recomend/637_1. [Accessed: 20.04.2024].

13. Laasanen J., Romppanen E.L., Hiltunen M. et al. Two exonic single nucleotide polymorphisms in the microsomal epoxide hydrolase gene are jointly associated with preeclampsia. Eur J Hum Genet. 2002;10(9):569–73. https://doi.org/10.1038/sj.ejhg.5200849.

14. Timofeeva A.V., Gusar V.A., Kan N.E. et al. Identification of potential early biomarkers of preeclampsia. Placenta. 2018;61:61–71. https://doi.org/10.1016/j.placenta.2017.11.011.

15. Iacobelli S., Bonsante F., Robillard P.-V. Comparison of risk factors and perinatal outcomes in early onset and late onset preeclampsia: a cohort based study in Reunion Island. J Reprod Immunol. 2017;123:12–6. https://doi.org/10.1016/j.jri.2017.08.005.

16. Jardim L., Rios D., Perucci L. et al. Is the imbalance between pro-angiogenic and anti-angiogenic factors associated with preeclampsia? Clini Chim Acta. 2015;447:34–8. https://doi.org/10.1016/j.cca.2015.05.004.

17. Panaitescu A., Syngelaki A., Prodan N. et al. Chronic hypertension and adverse pregnancy outcome: a cohort study. Ultrasound Obstet Gynecol. 2017;50(2):228–35. https://doi.org/10.1002/uog.17554.

18. Donker R.B., Mouillet J.-F., Nelson D.M., Sadovsky Y. The expression of Argonaute2 and related microRNA biogenesis proteins in normal and hypoxic trophoblasts. Mol Hum Reprod. 2007;13(4):273–9. https://doi.org/10.1093/molehr/gam006.

19. Ji L., Brkić J., Liu M. et al. Placental trophoblast cell differentiation: physiological regulation and pathological relevance to preeclampsia. Mol Asp Med. 2013;34(5):981–1023. https://doi.org/10.1016/j.mam.2012.12.008.

20. Seitz H., Royo H., Bortolin M.-L. et al. A large imprinted microRNA gene cluster at the mouse Dlk1-Gtl2 domain. Genome Res. 2004;14(9):1741–8. https://doi.org/10.1101/gr.2743304.

21. Yin Y., Liu M., Yu H. et al. Circulating microRNAs as biomarkers for diagnosis and prediction of preeclampsia: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2020;253:121–32. https://doi.org/10.1016/j.ejogrb.2020.08.016.

22. Lu Q., Ma Z., Ding Y. et al. Circulating miR-103a-3p contributes to angiotensin II-induced renal inflammation and fibrosis via a SNRK/NF-κB/p65 regulatory axis. Nat Commun. 2019;10(1):2145. https://doi.org/10.1038/s41467-019-10116-0.

23. Zhang C., Zhang C., Wang H. et al. Effects of miR-103a-3p on the autophagy and apoptosis of cardiomyocytes by regulating Atg5. Int J Mol Med. 2019;43(5):1951–60. https://doi.org/10.3892/ijmm.2019.4128.

24. He L., Xu J., Bai Y. et al. MicroRNA-103a regulates the calcification of vascular smooth muscle cells by targeting runt-related transcription factor 2 in high phosphorus conditions. Exp Ther Med. 2021;22(3):1036. https://doi.org/10.3892/etm.2021.10468.

25. Pakin V.S., Vashukova E.S., Kapustin R.V. et al. Peculiarities of placental microRNA expression in pregnancies complicated by gestational diabetes mellitus and preeclampsia. [Ocenka urovnya mikroRNK v placente pri tyazhelom gestoze na fone gestacionnogo saharnogo diabeta]. Zhurnal akusherstva i zhenskih boleznej. 2017;66(3):110–5. (In Russ.). https://doi.org/10.17816/JOWD663110-115.

26. Li T., Mo X., Fu L. et al. Molecular mechanisms of long noncoding RNAs on gastric cancer. Oncotarget. 2016;7(8):8601–12. https://doi.org/10.18632/oncotarget.6926.

27. Madsen H., Ditzel J. Blood-oxygen transport in first trimester of diabetic pregnancy. Acta Obstet Gynecol Scand. 1984;63(4):317–20. https://doi.org/10.3109/00016348409155523.

28. Ishibashi O., Ohkuchi A., Ali M.M. et al. Hydroxysteroid (17-β) dehydrogenase 1 is dysregulated by miR-210 and miR-518c that are aberrantly expressed in preeclamptic placentas: a novel marker for predicting preeclampsia. Hypertension. 2012;59(2):265–73. https://doi.org/10.1161/HYPERTENSIONAHA.111.180232.

29. Timofeeva A.V., Fedorov I.S., Sukhova Y.V. et al. Prediction of early- and late-onset pre-eclampsia in the preclinical stage via placenta-specific extracellular miRNA profiling. Int J Mol Sci. 2023;24(9):8006. https://doi.org/10.3390/ijms24098006.

30. Inno R., Kikas T., Lillepea K., Laan M. Coordinated expressional landscape of the human placental miRNome and transcriptome. Front Cell Dev Biol. 2021;9:697947. https://doi.org/10.3389/fcell.2021.697947.