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The bivariate NRIP1/ZEB2 RNA marker permits non-invasive presymptomatic screening of pre-eclampsia.

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.

SUBMITTER: Manders V

PROVIDER: S-EPMC7736279 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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The bivariate NRIP1/ZEB2 RNA marker permits non-invasive presymptomatic screening of pre-eclampsia.

Manders Vera V Visser Allerdien A Keijser Remco R Min Naomi N Poutsma Ankie A Mulders Joyce J van den Berkmortel Tarah T Hortensius Marjolein M Jongejan Aldo A Pajkrt Eva E Sistermans Erik A EA Sie Daoud D Best Myron G MG Würdinger Tom T de Boer Marjon M Afink Gijs G Oudejans Cees C

Scientific reports 20201214 1

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-preg ...[more]

PMID: 33318568

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Project description:ObjectivesPreterm birth (PTB) is a major public health problem worldwide. It can occur spontaneously or be medically indicated for obstetric complications, such as pre-eclampsia (PE) or fetal growth restriction. The main objective of this study was to investigate whether there is a shared uteroplacental etiology in the first trimester of pregnancy across PTB subtypes.MethodsThis was a retrospective cohort study of singleton pregnancies that underwent screening for preterm PE as part of their routine first-trimester ultrasound assessment at a tertiary center in London, UK, between March 2018 and December 2020. Screening for preterm PE was performed using the Fetal Medicine Foundation algorithm, which includes maternal factors, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and pregnancy-associated plasma protein-A (PAPP-A). Women with a risk of ≥ 1 in 50 for preterm PE were classified as high risk and offered prophylactic aspirin (150 mg once a day) and serial ultrasound assessments. The following delivery outcomes were evaluated: PTB < 37 weeks, iatrogenic PTB (iPTB) and spontaneous PTB (sPTB). Logistic regression analyses were performed to assess the association of PTB, iPTB and sPTB with an increased risk of preterm PE. A model for prediction of PTB < 37 weeks and < 33 weeks was developed and its performance was compared with that of an existing model in the literature.ResultsA total of 11 437 women were included in the study, of whom 475 (4.2%) had PTB. Of these, 308 (64.8%) were sPTB and 167 (35.2%) were iPTB. Patients with PTB had a higher body mass index, were more likely to be of black or Asian ethnicity, be smokers, have pregestational hypertension or diabetes, or have a history of previous PTB. They also had higher MAP (87.7 vs 86.0 mmHg, P < 0.0001), higher UtA-PI multiples of the median (MoM) (0.99 vs 0.92, P < 0.0001) and lower PAPP-A MoM (0.89 vs 1.08, P < 0.0001) compared to women with a term birth. In women at high risk of PE, the odds ratio for iPTB was 6.0 (95% CI, 4.29-8.43; P < 0.0001) and that for sPTB was 2.0 (95% CI, 1.46-2.86; P < 0.0001). A prediction model for PTB < 37 weeks and < 33 weeks, developed based on this cohort, included previous PTB, black ethnicity, chronic hypertension, diabetes mellitus, PAPP-A MoM and UtA-PI MoM. The performance of the model was similar to that of an existing first-trimester prediction model for PTB < 33 weeks (area under the curve, 0.704 (95% CI, 0.653-0.754) vs 0.694 (95% CI, 0.643-0.746)).ConclusionsIncreased first-trimester risk for uteroplacental dysfunction was associated with both iPTB and sPTB, implying a shared etiological pathway. The same factors used to predict PE risk show acceptable discrimination to predict PTB at < 33 weeks. Women at high risk of uteroplacental dysfunction may warrant additional monitoring and management for an increased risk of sPTB. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Project description:BackgroundPre-eclampsia is the most common complication occurring during pregnancy. In the majority of cases, it is concurrent with other pathologies in a comorbid manner (frequent co-occurrences in patients), such as diabetes mellitus, gestational diabetes and obesity. Providing bronchial asthma, pulmonary tuberculosis, certain neurodegenerative diseases and cancers as examples, we have shown previously that pairs of inversely comorbid pathologies (rare co-occurrences in patients) are more closely related to each other at the molecular genetic level compared with randomly generated pairs of diseases. Data in the literature concerning the causes of pre-eclampsia are abundant. However, the key mechanisms triggering this disease that are initiated by other pathological processes are thus far unknown. The aim of this work was to analyse the characteristic features of genetic networks that describe interactions between comorbid diseases, using pre-eclampsia as a case in point.ResultsThe use of ANDSystem, Pathway Studio and STRING computer tools based on text-mining and database-mining approaches allowed us to reconstruct associative networks, representing molecular genetic interactions between genes, associated concurrently with comorbid disease pairs, including pre-eclampsia, diabetes mellitus, gestational diabetes and obesity. It was found that these associative networks statistically differed in the number of genes and interactions between them from those built for randomly chosen pairs of diseases. The associative network connecting all four diseases was composed of 16 genes (PLAT, ADIPOQ, ADRB3, LEPR, HP, TGFB1, TNFA, INS, CRP, CSRP1, IGFBP1, MBL2, ACE, ESR1, SHBG, ADA). Such an analysis allowed us to reveal differential gene risk factors for these diseases, and to propose certain, most probable, theoretical mechanisms of pre-eclampsia development in pregnant women. The mechanisms may include the following pathways: [TGFB1 or TNFA]-[IL1B]-[pre-eclampsia]; [TNFA or INS]-[NOS3]-[pre-eclampsia]; [INS]-[HSPA4 or CLU]-[pre-eclampsia]; [ACE]-[MTHFR]-[pre-eclampsia].ConclusionsFor pre-eclampsia, diabetes mellitus, gestational diabetes and obesity, we showed that the size and connectivity of the associative molecular genetic networks, which describe interactions between comorbid diseases, statistically exceeded the size and connectivity of those built for randomly chosen pairs of diseases. Recently, we have shown a similar result for inversely comorbid diseases. This suggests that comorbid and inversely comorbid diseases have common features concerning structural organization of associative molecular genetic networks.

Dataset Information

The bivariate NRIP1/ZEB2 RNA marker permits non-invasive presymptomatic screening of pre-eclampsia.

Publications

The bivariate NRIP1/ZEB2 RNA marker permits non-invasive presymptomatic screening of pre-eclampsia.

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