Dataset Information

Non-invasive prediction of fetal growth restriction by whole-genome promoter profiling of maternal plasma DNA: a nested case-control study.

ABSTRACT:

Objective

To predict fetal growth restriction (FGR) by whole-genome promoter profiling of maternal plasma.

Design

Nested case-control study.

Setting

Hospital-based.

Population or sample

810 pregnancies: 162 FGR cases and 648 controls.

Methods

We identified gene promoters with a nucleosome footprint that differed between FGR cases and controls based on maternal plasma cell-free DNA (cfDNA) nucleosome profiling. Optimal classifiers were developed using support vector machine (SVM) and logistic regression (LR) models.

Main outcome measures

Genes with differential coverages in promoter regions through the low-coverage whole-genome sequencing data analysis among FGR cases and controls. Receiver operating characteristic (ROC) analysis (area under the curve [AUC], accuracy, sensitivity and specificity) was used to evaluate the performance of classifiers.

Results

Through the low-coverage whole-genome sequencing data analysis of FGR cases and controls, genes with significantly differential DNA coverage at promoter regions (-1000 to +1000 bp of transcription start sites) were identified. The non-invasive 'FGR classifier 1' (C_FGR 1) had the highest classification performance (AUC, 0.803; 95% CI 0.767-0.839; accuracy, 83.2%) was developed based on 14 genes with differential promoter coverage using a support vector machine.

Conclusions

A promising FGR prediction method was successfully developed for assessing the risk of FGR at an early gestational age based on maternal plasma cfDNA nucleosome profiling.

Tweetable abstract

A promising FGR prediction method was successfully developed, based on maternal plasma cfDNA nucleosome profiling.

SUBMITTER: Xu C

PROVIDER: S-EPMC7818264 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Publications

Non-invasive prediction of fetal growth restriction by whole-genome promoter profiling of maternal plasma DNA: a nested case-control study.

Xu C C Guo Z Z Zhang J J Lu Q Q Tian Q Q Liu S S Li K K Wang K K Tao Z Z Li C C Lv Z Z Zhang Z Z Yang X X Yang F F

BJOG : an international journal of obstetrics and gynaecology 20200602 2

<h4>Objective</h4>To predict fetal growth restriction (FGR) by whole-genome promoter profiling of maternal plasma.<h4>Design</h4>Nested case-control study.<h4>Setting</h4>Hospital-based.<h4>Population or sample</h4>810 pregnancies: 162 FGR cases and 648 controls.<h4>Methods</h4>We identified gene promoters with a nucleosome footprint that differed between FGR cases and controls based on maternal plasma cell-free DNA (cfDNA) nucleosome profiling. Optimal classifiers were developed using support v ...[more]

PMID: 32364311

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Project description:BackgroundDown syndrome (DS) is the most common known aneuploidy, caused by an extra copy of all or part of chromosome 21. Fetal-specific epigenetic markers have been investigated for non-invasive prenatal detection of fetal DS. The phosphodiesterases gene, PDE9A, located on chromosome 21q22.3, is completely methylated in blood (M-PDE9A) and unmethylated in the placenta (U-PDE9A). Therefore, we estimated the accuracy of non-invasive fetal DS detection during the first trimester of pregnancy using this tissue-specific epigenetic characteristic of PDE9A.Methodology/principal findingsA nested, case-control study was conducted using maternal plasma samples collected from 108 pregnant women carrying 18 DS and 90 normal fetuses (each case was matched with 5 controls according to gestational weeks at blood sampling). All pregnancies were singletons at or before 12 weeks of gestation between October 2008 and May 2009. The maternal plasma levels of M-PDE9A and U-PDE9A were measured by quantitative methylation-specific polymerase chain reaction. M-PDE9A and U-PDE9A levels were obtained in all samples and did not differ between male and female fetuses. M-PDE9A levels did not differ between the DS cases and controls (1854.3 vs 2004.5 copies/mL; P?=?0.928). U-PDE9A levels were significantly elevated in women with DS fetuses compared with controls (356.8 vs 194.7 copies/mL, P<0.001). The sensitivities of U-PDE9A level and the unmethylation index of PDE9A for non-invasive fetal DS detection were 77.8% and 83.3%, respectively, with a 5% false-positive rate. In the risk assessment for fetal DS, the adjusted odds ratios of U-PDE9A level and UI were 46.2 [95% confidence interval: 7.8-151.6] and 63.7 [95% confidence interval: 23.2-206.7], respectively.ConclusionsOur findings suggest that U-PDE9A level and the unmethylation index of PDE9A may be useful biomarkers for non-invasive fetal DS detection during the first trimester of pregnancy, regardless of fetal gender.

Project description:Introduction: Fetal growth restriction (FGR) is a placenta-mediated pregnancy complication that predisposes fetuses to perinatal complications. Maternal plasma cell-free DNA harbors DNA originating from placental trophoblasts, which is promising for the prenatal diagnosis and prediction of pregnancy complications. Extrachromosomal circular DNA (eccDNA) is emerging as an ideal biomarker and target for several diseases. Methods: We utilized eccDNA sequencing and bioinformatic pipeline to investigate the characteristics and associations of eccDNA in placenta and maternal plasma, the role of placental eccDNA in the pathogenesis of FGR, and potential plasma eccDNA biomarkers of FGR. Results: Using our bioinformatics pipelines, we identified multi-chromosomal-fragment and single-fragment eccDNA in placenta, but almost exclusively single-fragment eccDNA in maternal plasma. Relative to that in plasma, eccDNA in placenta was larger and substantially more abundant in exons, untranslated regions, promoters, repetitive elements [short interspersed nuclear elements (SINEs)/Alu, SINEs/mammalian-wide interspersed repeats, long terminal repeats/endogenous retrovirus-like elements, and single recognition particle RNA], and transcription factor binding motifs. Placental multi-chromosomal-fragment eccDNA was enriched in confident enhancer regions predicted to pertain to genes in apoptosis, energy, cell growth, and autophagy pathways. Placental eccDNA-associated genes whose abundance differed between the FGR and control groups were associated with immunity-related gene ontology (GO) terms. The combined analysis of plasma and placental eccDNA-associated genes in the FGR and control groups led to the identification of potential biomarkers that were assigned to the GO terms of the epigenetic regulation of gene expression and nutrient-related processes, respectively. Conclusion: Together, our results highlight links between placenta functions and multi-chromosomal-fragment and single-fragment eccDNA. The integrative analysis of placental and plasma eccDNA confirmed the potential of these molecules as disease-specific biomarkers of FGR.

Project description:BACKGROUND:Placental mRNA was detected in maternal whole blood, raising the possibility of using maternal blood for noninvasive prenatal diagnosis. We investigated fetal mRNA detection in maternal whole blood and determined if it offered advantages over maternal plasma analysis. METHODOLOGY:The concentrations of placental expressed genes, CSH1, KISS1, PLAC4 and PLAC1 in plasma and whole blood from healthy pregnant and non-pregnant individuals were compared by real-time quantitative reverse-transcriptase polymerase chain reaction analysis. Their fetal specificity was investigated by comparing the transcript concentrations in pre- and post-delivery samples and through SNP genotyping by matrix-assisted laser-desorption and ionization time-of-flight mass spectrometry. The gene expression profiles of pregnant and non-pregnant whole blood were investigated by microarray analysis. Upregulated genes in pregnant whole blood were selected for further quantitative analysis. PRINCIPAL FINDINGS:The concentrations of the four transcripts were significantly higher in third trimester maternal whole blood than corresponding plasma without significant correlations. KISS1, PLAC4 and PLAC1 were detected in non-pregnant whole blood but not plasma. The transcripts remained detectable in some postpartum whole blood samples. The PLAC4 mRNA in maternal plasma showed fetal genotype while that in corresponding whole blood indicated both fetal and maternal contributions. Microarray analysis revealed upregulation of genes involved in neutrophil functions in pregnant whole blood including DEFA4, CEACAM8, OLFM4, ORM1, MMP8 and MPO. Though possibly pregnancy-related, they were not pregnancy-specific as suggested by the lack of post-delivery reduction in concentrations. CONCLUSIONS:Maternal plasma is preferred over maternal whole blood for placenta-derived fetal RNA detection. Most studied 'placental' mRNA molecules in maternal whole blood were of maternal origin and might be derived from processes such as 'illegitimate transcription'.

Dataset Information

Non-invasive prediction of fetal growth restriction by whole-genome promoter profiling of maternal plasma DNA: a nested case-control study.

Objective

Design

Setting

Population or sample

Methods

Main outcome measures

Results

Conclusions

Tweetable abstract

Publications

Non-invasive prediction of fetal growth restriction by whole-genome promoter profiling of maternal plasma DNA: a nested case-control study.

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