Dataset Information

Discovery and Verification of Extracellular miRNA Biomarkers for Non-invasive Prediction of Pre-eclampsia in Asymptomatic Women.

ABSTRACT: Development of effective prevention and treatment strategies for pre-eclampsia is limited by the lack of accurate methods for identification of at-risk pregnancies. We performed small RNA sequencing (RNA-seq) of maternal serum extracellular RNAs (exRNAs) to discover and verify microRNAs (miRNAs) differentially expressed in patients who later developed pre-eclampsia. Sera collected from 73 pre-eclampsia cases and 139 controls between 17 and 28 weeks gestational age (GA), divided into separate discovery and verification cohorts, are analyzed by small RNA-seq. Discovery and verification of univariate and bivariate miRNA biomarkers reveal that bivariate biomarkers verify at a markedly higher rate than univariate biomarkers. The majority of verified biomarkers contain miR-155-5p, which has been reported to mediate the pre-eclampsia-associated repression of endothelial nitric oxide synthase (eNOS) by tumor necrosis factor alpha (TNF-α). Deconvolution analysis reveals that several verified miRNA biomarkers come from the placenta and are likely carried by placenta-specific extracellular vesicles.

SUBMITTER: Srinivasan S

PROVIDER: S-EPMC7455024 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Discovery and Verification of Extracellular miRNA Biomarkers for Non-invasive Prediction of Pre-eclampsia in Asymptomatic Women.

Srinivasan Srimeenakshi S Treacy Ryan R Herrero Tiffany T Olsen Richelle R Leonardo Trevor R TR Zhang Xuan X DeHoff Peter P To Cuong C Poling Lara G LG Fernando Aileen A Leon-Garcia Sandra S Knepper Katharine K Tran Vy V Meads Morgan M Tasarz Jennifer J Vuppala Aishwarya A Park Soojin S Laurent Clara D CD Bui Tony T Cheah Pike See PS Overcash Rachael Tabitha RT Ramos Gladys A GA Roeder Hilary H Ghiran Ionita I Parast Mana M Breakefield Xandra O XO Lueth Amir J AJ Rust Sharon R SR Dufford Max T MT Fox Angela C AC Hickok Durlin E DE Burchard Julja J Boniface J Jay JJ Laurent Louise C LC

Cell reports. Medicine 20200501 2

Development of effective prevention and treatment strategies for pre-eclampsia is limited by the lack of accurate methods for identification of at-risk pregnancies. We performed small RNA sequencing (RNA-seq) of maternal serum extracellular RNAs (exRNAs) to discover and verify microRNAs (miRNAs) differentially expressed in patients who later developed pre-eclampsia. Sera collected from 73 pre-eclampsia cases and 139 controls between 17 and 28 weeks gestational age (GA), divided into separate dis ...[more]

PMID: 32864636

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Project description:Pre-eclampsia (PE) is one of the severe complications of pregnancy in 3-8% of all cases and is one of the leading causes of maternal and perinatal mortality. The fundamental role in the pathogenesis of PE is assigned to maternal and/or placental factors, whereby the combination and manifestation of which determines the time of onset of the clinical symptoms of PE (before or after 34 weeks of gestation) and their severity. It is known that the expression level of miRNAs, the regulators of signaling cascades in the cell, depends on gestational age. In the present study, we focused on the identification of the placenta-specific miRNAs that differentiate between early- and late-onset pre-eclampsia (ePE and lPE) throughout pregnancy, from the first to the third trimester. A total of 67 patients were analyzed using small RNA deep sequencing and real-time quantitative PCR, which resulted in a core list of miRNAs (let-7b-5p, let-7d-3p, let-7f-5p, let-7i-5p, miR-22-5p, miR-451a, miR-1246, miR-30e-5p, miR-20a-5p, miR-1307-3p, and miR-320e), which in certain combinations can predict ePE or lPE with 100% sensitivity and 84-100% specificity in the 1st trimester of pregnancy. According to the literature data, these miRNA predictors of PE control trophoblast proliferation, invasion, migration, syncytialization, the endoplasmic reticulum unfolded protein response, immune tolerance, angiogenesis, and vascular integrity. The simultaneous detection of let-7d-3p, miR-451a, and miR-1307-3p, resistant to the repeated freezing/thawing of blood serum samples, in combination with biochemical (b-hCG and PAPP-A) and ultrasound (UAPI) parameters, allowed us to develop a universal model for the prediction of ePE and lPE onset (FPR = 15.7% and FNR = 9.5%), which was validated using a test cohort of 48 patients and demonstrated false-positive results in 26.7% of cases and false negatives in 5.6% of cases. For comparison, the use of the generally accepted Astraia program in the analysis of the test cohort of patients led to worse results: FPR = 62.1% and FNR = 33.3%.

Project description:ObjectiveThis study aimed to develop a blood test for the prediction of pre-eclampsia (PE) early in gestation. We hypothesised that the longitudinal measurements of circulating adipokines and sphingolipids in maternal serum over the course of pregnancy could identify novel prognostic biomarkers that are predictive of impending event of PE early in gestation.Study designRetrospective discovery and longitudinal confirmation.SettingMaternity units from two US hospitals.ParticipantsSix previously published studies of placental tissue (78 PE and 95 non-PE) were compiled for genomic discovery, maternal sera from 15 women (7 non-PE and 8 PE) enrolled at ProMedDx were used for sphingolipidomic discovery, and maternal sera from 40 women (20 non-PE and 20 PE) enrolled at Stanford University were used for longitudinal observation.Outcome measuresBiomarker candidates from discovery were longitudinally confirmed and compared in parallel to the ratio of placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) using the same cohort. The datasets were generated by enzyme-linked immunosorbent and liquid chromatography-tandem mass spectrometric assays.ResultsOur discovery integrating genomic and sphingolipidomic analysis identified leptin (Lep) and ceramide (Cer) (d18:1/25:0) as novel biomarkers for early gestational assessment of PE. Our longitudinal observation revealed a marked elevation of Lep/Cer (d18:1/25:0) ratio in maternal serum at a median of 23 weeks' gestation among women with impending PE as compared with women with uncomplicated pregnancy. The Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting impending event of PE with superior sensitivity (85% vs 20%) and area under curve (0.92 vs 0.52) from 5 to 25 weeks of gestation.ConclusionsOur study demonstrated the longitudinal measurement of maternal Lep/Cer (d18:1/25:0) ratio allows the non-invasive assessment of PE to identify pregnancy at high risk in early gestation, outperforming the established sFlt-1/PlGF ratio test.

Project description:ObjectiveA model that can predict reliably the risk of pre-eclampsia (PE)-related pregnancy complications does not exist. The aim of this study was to develop and validate internally a clinical prediction model to predict the risk of a composite outcome of PE-related maternal and fetal complications within 7, 14 and 30 days of testing in women with suspected or confirmed PE.MethodsThe data for this study were derived from a prospective, multicenter, observational cohort study on women with a singleton pregnancy and suspected or confirmed PE at 20 to < 37 weeks' gestation. For the development of the prediction model, the possible contribution of clinical and standard laboratory variables, as well as the biomarkers soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and their ratio, in the prediction of a composite outcome of PE-related complications, consisting of maternal and fetal adverse events within 7, 14 and 30 days, was explored using multivariable competing-risks regression analysis. The discriminative ability of the model was assessed using the concordance (c-) statistic. A bootstrap validation procedure with 500 replications was used to correct the estimate of the prediction model performance for optimism and to compute a shrinkage factor for the regression coefficients to correct for overfitting.ResultsAmong 384 women with suspected or confirmed PE, 96 (25%) had an adverse PE-related outcome at any time after hospital admission. Important predictors of adverse PE-related outcome included sFlt-1/PlGF ratio, gestational age at the time of biomarker measurement and protein-to-creatinine ratio as continuous variables. The c-statistics (corrected for optimism) for developing a PE-related complication within 7, 14 and 30 days were 0.89, 0.88 and 0.87, respectively. There was limited overfitting, as indicated by a shrinkage factor of 0.91.ConclusionsWe propose a simple clinical prediction model with good discriminative performance to predict PE-related complications. Determination of its usefulness in clinical practice awaits further investigation and external validation. © 2020 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:ObjectiveA high ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) has been linked to pre-eclampsia (PE). We evaluated the sFlt-1/PlGF ratio as a predictive marker for early-onset PE in women at risk of PE.MethodsThis prospective, Spanish, multicenter study included pregnant women with a risk factor for PE, including intrauterine growth restriction, PE, eclampsia or hemolysis, elevated liver enzymes and low platelet count syndrome in previous pregnancy, pregestational diabetes or abnormal uterine artery Doppler. The primary objective was to show that the sFlt-1/PlGF ratio at 20, 24 and 28 weeks' gestation was predictive of early-onset PE (< 34 + 0 weeks). Serum sFlt-1 and PlGF were measured at 20, 24 and 28 weeks. Multivariate logistic regression was used to develop a predictive model.ResultsA total of 819 women were enrolled, of which 729 were suitable for analysis. Of these, 78 (10.7%) women developed PE (24 early onset and 54 late onset). Median sFlt-1/PlGF ratio at 20, 24 and 28 weeks was 6.3 (interquartile range (IQR), 4.1-9.3), 4.0 (IQR, 2.6-6.3) and 3.3 (IQR, 2.0-5.9), respectively, for women who did not develop PE (controls); 14.5 (IQR, 5.5-43.7), 18.4 (IQR, 8.2-57.9) and 51.9 (IQR, 11.5-145.6) for women with early-onset PE; and 6.7 (IQR, 4.6-9.9), 4.7 (IQR, 2.8-7.2) and 6.0 (IQR, 3.8-10.5) for women with late-onset PE. Compared with early-onset PE, the sFlt-1/PlGF ratio was significantly lower in controls (P < 0.001 at each timepoint) and in women with chronic hypertension (P < 0.001 at each timepoint), gestational hypertension (P < 0.001 at each timepoint) and late-onset PE (P < 0.001 at each timepoint). A prediction model for early-onset PE was developed, which included the sFlt-1/PlGF ratio plus mean arterial pressure, being parous and previous PE, with areas under the receiver-operating characteristics curves of 0.86 (95% CI, 0.77-0.95), 0.91 (95% CI, 0.85-0.97) and 0.93 (95% CI, 0.86-0.99) at 20, 24 and 28 weeks, respectively, and was superior to models using the sFlt-1/PlGF ratio alone or uterine artery mean pulsatility index.ConclusionsThe sFlt-1/PlGF ratio can improve prediction of early-onset PE for women at risk of this condition. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Dataset Information

Discovery and Verification of Extracellular miRNA Biomarkers for Non-invasive Prediction of Pre-eclampsia in Asymptomatic Women.

Publications

Discovery and Verification of Extracellular miRNA Biomarkers for Non-invasive Prediction of Pre-eclampsia in Asymptomatic Women.

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