RNA biotypes linked to preeclampsia

RNA biotypes linked to preeclampsia | Image Credit: © Sukjai Photo - © Sukjai Photo - stock.adobe.com.

According to a recent study published in the American Journal of Obstetrics and Gynecology, preeclampsia (PE) can be predicted using RNA biotypes including messenger RNA (mRNA), microRNA (miRNA), and long noncoding RNA (lncRNA).

PE is defined as, “the onset of new hypertension and proteinuria or other end-organ damage,” impacting 2% to 4% of pregnant women worldwide. Presenting after 20 weeks of pregnancy, it is associated with 46,000 maternal deaths and 500,000 fetal and newborn deaths annually.

Early-onset PE has been associated with increased risk of placental dysfunction, including fetal growth limitation. Most literature on PE focuses on preterm PE, which makes up one-third of all PE cases and presents an increased risk of maternal and neonatal complications.

PE development has been observed as abnormal placental development in early pregnancy and systemic maternal endothelial dysregulation and inflammation. While it is currently difficult to predict, treat, and prevent PE, circulating cell-free RNA (cfRNA) may allow for new opportunities in understanding PE. This includes mRNA, miRNA, and lncRNA.

Data has indicated cfRNA may be used as a noninvasive biomarker for PE. However, it is necessary to understand how various RNA types function as biomarkers. Investigators conducted a study to investigate PE-associated cfRNA and develop classifiers for predicting preterm PE and early-onset PE.

The study included 917 pregnancies from the Shenzhen Longgang Maternal and Child Health Care Hospital (LGH) and Shenzhen Baoan Maternal and Child Health Care Hospital (BAH). Of pregnancies, 202 were observed with preterm PE while 715 were healthy.

Plasma collection occurred at the LGH from January 1, 2018, to March 1, 2022. There were 3 cohorts in the validation stage: the internal validation cohort 3 recruited from the LGH and the external validation cohorts 4 and 5 recruited from the BAH. Antenatal blood sample collection occurred before diagnosis and between 12 and 33 weeks of gestation.

Pregnancies reaching full term without complications were considered normotensive and matched with PE pregnancies. Exclusion criteria included chronic hypertension, pregestational diabetes, autoimmune diseases, kidney-related diseases, smoking history, alcohol consumption during pregnancy, and pregnancies ending in miscarriage, termination, or fetal death before 24 weeks of gestation.

BD Vacutainer spray-coated K2EDTA tubes were used to collect whole blood, with plasma separation taking place within 6 hours after collection. The PALM-seq protocol, capable of capturing lncRNA, mRNA, and small RNA with high complexity, was used to develop an RNA library.

Early-onset PE was defined as PE before 34 weeks of gestation, while preterm PE was defined as PE in pregnant women who delivered before 37 weeks of gestation. PE diagnosis was based on guidelines from American College of Obstetricians and Gynecologists.

A ratio of about 1:4 was found between women with PE and women with healthy pregnancy. There were 2 discovery cohorts and 3 validation cohorts. Discovery cohort 1 was matched with validation cohorts 3 and 5 to identify preterm PE, while discovery cohort 2 was matched with validation cohort 4 to identify early-onset PE.

While body mass index, parity, and age have been associated with increased PE risk, these characteristics did not significantly differ between PE and control groups. However, methods of conception differed between groups.

Preterm delivery was found in mothers who developed early-onset PE compared to the normotensive group, along with earlier delivery than mothers with preterm PE. Lower fetal weights were also seen in the preterm PE and early-onset PE groups compared to the normotensive group.

Increased cfRNA signatures were found among PE plasma samples compared to normotensive samples, including 44% mRNA and 26% miRNA. In PE samples, increased levels of mRNA expression associated with bone marrow, liver, kidney, brain, skeletal muscle, and lymphoid tissue were seen.

In discovery cohort 2, mRNAs and miRNAs were the most frequently observed RNA types, with 81% of mRNAs being tissue specific. Differentially expressed genes found were linked to known PE etiologies.

These results showed associations between cfRNA signatures and PE. Investigators recommended future studies to determine if the classifiers used in this study could be used in clinical practice.

Reference

Zhou S, Li J, Yang W. Noninvasive preeclampsia prediction using plasma cell–free RNA signatures. American Journal of Obstetrics and Gynecology. 2023. doi:10.1016/j.ajog.2023.05.015