Abstract
Using genome-wide transcriptome analysis by RNA sequencing of first trimester plasma RNA, we tested whether the identification of pregnancies at risk of developing pre-eclampsia with or without preterm birth or growth restriction is possible between weeks 9–14, prior to the appearance of clinical symptoms. We implemented a metaheuristic approach in the self-learning SVM algorithm for differential gene expression analysis of normal pregnancies (n = 108), affected pregnancies (n = 34) and non-pregnant controls (n = 19). Presymptomatic candidate markers for affected pregnancies were validated by RT-qPCR in first trimester samples (n = 34) from an independent cohort. PRKG1 was significantly downregulated in a subset of pregnancies with birth weights below the 10thpercentile as shared symptom. The NRIP1/ZEB2 ratio was found to be upregulated in pregnancies with pre-eclampsia or trisomy 21. Complementary quantitative analysis of both the linear and circular forms of NRIP1 permitted discrimination between pre-eclampsia and trisomy 21. Pre-eclamptic pregnancies showed an increase in linear NRIP1 compared to circular NRIP1, while trisomy 21 pregnancies did not.
Highlights
Maternal plasma RNA sequencing allows non-invasive in vivo monitoring of placental function[1,2,3]
We applied a metaheuristic strategy for maternal plasma RNA sequencing analysis to test if the identification of pregnancies at risk is possible prior to the presence of clinical symptoms
Out of 1115 plasma samples available, a randomly chosen subset (n = 221) of this cohort was subjected to stranded, pairedend RNA sequencing of plasma RNA. This subset was subjected to RNA sequencing prior to delivery i.e. without knowledge of pregnancy outcome during selection
Summary
Maternal plasma RNA sequencing allows non-invasive in vivo monitoring of placental function[1,2,3]. When complemented with single-cell RNA sequencing of the placental and maternal cells that contribute to the pool of cellfree RNA in plasma, the cell-specific gene signatures yield a bioinformatic barcode for non-invasive diagnostics of pregnancy-associated diseases with placental insufficiency[3] This was demonstrated using the gene signature for the extravillous trophoblast, allowing molecular confirmation of pre-eclampsia at the symptomatic s tage[3]. A prerequisite to be clinically effective for diagnostics, risk classification and therapy is to have any RNA-based screening method be applicable and informative in the first trimester This gestational period during which the essential vascular connection between mother and fetus is established and the placenta becomes fully hemochorial, is the time window of the pathophysiological start of the majority of pregnancy-associated diseases with placental insufficiency[6]. We applied a metaheuristic strategy for maternal plasma RNA sequencing analysis to test if the identification of pregnancies at risk is possible prior to the presence of clinical symptoms
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