Circulating transcripts in maternal blood reflect a molecular signature of early-onset preeclampsia

Abstract

<jats:p>Circulating RNA (C-RNA) is continually released into the bloodstream from tissues throughout the body, offering an opportunity to noninvasively monitor all aspects of pregnancy health from conception to birth. We asked whether C-RNA analysis could robustly detect aberrations in patients diagnosed with preeclampsia (PE), a prevalent and potentially fatal pregnancy complication. As an initial examination, we sequenced the circulating transcriptome from 40 pregnancies at the time of severe, early-onset PE diagnosis and 73 gestational age–matched controls. Differential expression analysis identified 30 transcripts with gene ontology annotations and tissue expression patterns consistent with the placental dysfunction, impaired fetal development, and maternal immune and cardiovascular system dysregulation characteristic of PE. Furthermore, machine learning identified combinations of 49 C-RNA transcripts that classified an independent cohort of patients (early-onset PE, <jats:italic>n</jats:italic> = 12; control, <jats:italic>n</jats:italic> = 12) with 85 to 89% accuracy. C-RNA may thus hold promise for improving the diagnosis and identification of at-risk pregnancies.</jats:p>

Investigating Pregnancy and Its Complications Using Circulating Cell-Free RNA in Women's Blood During Gestation

“…In general, it is defined as when expression of a gene in a single tissue can be measured exclusively or several fold (typically 2-20) above that from all other tissues. Using this definition, many genes detected prenatally originate from the placenta (9,11,19,20); however, other tissues and body systems also contribute measurably like fetal tissues and the maternal immune system (3,4,7,21,22).…”

“…Intriguingly, several groups have shown that cfRNA levels for specific pregnancy-related genes and circular RNAs change over gestation in predictable patterns (4,6). Late in gestation, some of these changes map closely with placental gene expression (9) or fetal organ function (7).…”

“…Longitudinal changes in gene expression follow three main trends: those that change continuously over pregnancy, those that change early in pregnancy and reach a plateau late in the second trimester, or, conversely, those that remain constant early in pregnancy only to change dramatically later in gestation (3,4,6,8). In uncomplicated full-term pregnancies, the cfRNA profiles of placental, maternal immune, and fetal tissue-specific genes correlate with those of other genes specific to the same body system.…”

“…More recently, in the past 5 years, we have witnessed unprecedented leaps in the applications of this technology to monitor prenatal health following its extension to measurements of circulating RNA in whole blood or cell-free RNA (cfRNA) in plasma. Today, circulating and cfRNA measurements have been applied to predict and characterize pregnancy-related complications like spontaneous preterm birth (PTB) (3), preeclampsia (4), and intrauterine growth restriction (IUGR) (5). In contrast to cfDNA levels, cfRNA levels of specific genes change during gestation in predictable ways that map closely with their placental and fetal gene expression (3,4,(6)(7)(8)(9).…”

“…Today, circulating and cfRNA measurements have been applied to predict and characterize pregnancy-related complications like spontaneous preterm birth (PTB) (3), preeclampsia (4), and intrauterine growth restriction (IUGR) (5). In contrast to cfDNA levels, cfRNA levels of specific genes change during gestation in predictable ways that map closely with their placental and fetal gene expression (3,4,(6)(7)(8)(9). These timed patterns provide a snapshot of prenatal health across gestation and can be leveraged to predict pregnancy-related complications months before clinical diagnoses can be made and perhaps even used to monitor fetal health.…”