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Transcriptomics of maternal and fetal membranes can discriminate between gestational-age matched preterm neonates with and without cognitive impairment diagnosed at 18-24 months.

ABSTRACT: Neurocognitive impairment among children born preterm may arise from complex interactions between genes and the intra-uterine environment.(1) To characterize the transcriptomic profiles of chorioamniotic membranes in preterm neonates with and without neurocognitive impairment via microarrays and (2) to determine if neonates with neurocognitive impairment can be identified at birth.A retrospective case-control study was conducted to examine the chorioamniotic transcriptome of gestational-age matched very preterm neonates with and without neurocognitive impairment at 18-24 months' corrected-age defined by a Bayley-III Cognitive Composite Score <80 (n = 14 each). Pathway analysis with down-weighting of overlapping genes (PADOG) was performed to identify KEGG pathways relevant to the phenotype. Select differentially expressed genes were profiled using qRT-PCR and a multi-gene disease prediction model was developed using linear discriminant analysis. The model's predictive performance was tested on a new set of cases and controls (n = 19 each).1) 117 genes were differentially expressed among neonates with and without subsequent neurocognitive impairment (p<0.05 and fold change >1.5); 2) Gene ontology analysis indicated enrichment of 19 biological processes and 3 molecular functions; 3)PADOG identified 4 significantly perturbed KEGG pathways: oxidative phosphorylation, Parkinson's disease, Alzheimer's disease and Huntington's disease (q-value <0.1); 4) 48 of 90 selected differentially expressed genes were confirmed by qRT-PCR, including genes implicated in energy metabolism, neuronal signaling, vascular permeability and response to injury (e.g., up-regulation of SEPP1, APOE, DAB2, CD163, CXCL12, VWF; down-regulation of HAND1, OSR1)(p<0.05); and 5) a multi-gene model predicted 18-24 month neurocognitive impairment (using the ratios of OSR1/VWF and HAND1/VWF at birth) in a larger, independent set (sensitivity = 74%, at specificity = 83%).Gene expression patterns in the chorioamniotic membranes link neurocognitive impairment in preterm infants to neurodegenerative disease pathways and might be used to predict neurocognitive impairment. Further prospective studies are needed.

SUBMITTER: Pappas A

PROVIDER: S-EPMC4379164 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Transcriptomics of maternal and fetal membranes can discriminate between gestational-age matched preterm neonates with and without cognitive impairment diagnosed at 18-24 months.

Pappas Athina A Chaiworapongsa Tinnakorn T Romero Roberto R Korzeniewski Steven J SJ Cortez Josef C JC Bhatti Gaurav G Gomez-Lopez Nardhy N Hassan Sonia S SS Shankaran Seetha S Tarca Adi L AL

PloS one 20150330 3

<h4>Background</h4>Neurocognitive impairment among children born preterm may arise from complex interactions between genes and the intra-uterine environment.<h4>Objectives</h4>(1) To characterize the transcriptomic profiles of chorioamniotic membranes in preterm neonates with and without neurocognitive impairment via microarrays and (2) to determine if neonates with neurocognitive impairment can be identified at birth.<h4>Materials/methods</h4>A retrospective case-control study was conducted to ...[more]

PMID: 25822971

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Project description:Background and purposeAdverse neurodevelopmental outcome is common in children born preterm. Early sensitive predictors of neurodevelopmental outcome such as MR imaging are needed. Tract-based spatial statistics, a diffusion MR imaging analysis method, performed at term-equivalent age (40 weeks) is a promising predictor of neurodevelopmental outcomes in children born very preterm. We sought to determine the association of tract-based spatial statistics findings before term-equivalent age with neurodevelopmental outcome at 18-months corrected age.Materials and methodsOf 180 neonates (born at 24-32-weeks' gestation) enrolled, 153 had DTI acquired early at 32 weeks' postmenstrual age and 105 had DTI acquired later at 39.6 weeks' postmenstrual age. Voxelwise statistics were calculated by performing tract-based spatial statistics on DTI that was aligned to age-appropriate templates. At 18-month corrected age, 166 neonates underwent neurodevelopmental assessment by using the Bayley Scales of Infant Development, 3rd ed, and the Peabody Developmental Motor Scales, 2nd ed.ResultsTract-based spatial statistics analysis applied to early-acquired scans (postmenstrual age of 30-33 weeks) indicated a limited significant positive association between motor skills and axial diffusivity and radial diffusivity values in the corpus callosum, internal and external/extreme capsules, and midbrain (P < .05, corrected). In contrast, for term scans (postmenstrual age of 37-41 weeks), tract-based spatial statistics analysis showed a significant relationship between both motor and cognitive scores with fractional anisotropy in the corpus callosum and corticospinal tracts (P < .05, corrected). Tract-based spatial statistics in a limited subset of neonates (n = 22) scanned at <30 weeks did not significantly predict neurodevelopmental outcomes.ConclusionsThe strength of the association between fractional anisotropy values and neurodevelopmental outcome scores increased from early-to-late-acquired scans in preterm-born neonates, consistent with brain dysmaturation in this population.

Project description:BackgroundWomen who develop diabetes during pregnancy are at higher risk of preterm birth. Here, we identified differentially expressed proteins (DEPs) in the serum of umbilical cord blood samples obtained from preterm neonates delivered by women with gestational diabetes to provide therapeutic targets for clinical drug development.Materials and methodsUmbilical cord blood was collected after delivery of preterm neonates by women with gestational diabetes and after delivery of healthy neonates by women without diabetes. DEPs in the serum samples were identified using liquid chromatography-tandem mass spectrometry. Gene Ontology (GO), cluster analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to determine the biological functions associated with these DEPs. Enzyme linked immunosorbent assay was used to confirm the key DEPs.ResultsWe found that 21 proteins were significantly upregulated, and 51 proteins were significantly downregulated in 72 DEPs in serum samples. GO analyses showed that the DEPs were mainly associated with the GO terms cellular process, biological regulation, cellular anatomical entity, and binding. KEGG signaling pathway analysis indicated that most of the upregulated DEPs were associated with the complement and coagulation cascades, Staphylococcus aureus infection, pertussis, HIF-1 signaling pathway and PPAR signaling pathway and that most of the downregulated DEPs were associated with the complement and coagulation cascades, dilated cardiomyopathy, pathways in cancer, Chagas disease, and hypertrophic cardiomyopathy. The results of KEGG pathway annotation and enrichment analyses indicated that changes in the complement and coagulation cascades may be importantly associated with preterm delivery of neonates by women with gestational diabetes. The key DEPs were confirmed by enzyme linked immunosorbent assay.ConclusionOur proteomics and bioinformatics analyses identified several key proteins and the complement and coagulation cascades pathway that warrant further investigation as potential novel therapeutic targets in preterm delivery among women with gestational diabetes.

Project description:BackgroundPreterm birth (PTB), or birth before 37 weeks of gestation, is the leading cause of newborn death worldwide. PTB is a critical area of scientific study not only due to its worldwide toll on human lives and economies, but also due to our limited understanding of its pathogenesis and, therefore, its prevention. This systematic review and meta-analysis synthesizes the landscape of PTB transcriptomics research to further our understanding of the genes and pathways involved in PTB subtypes.MethodsWe evaluated published genome-wide pregnancy studies across gestational tissues and pathologies, including those that focus on PTB, by performing a targeted PubMed MeSH search and systematically reviewing all relevant studies.ResultsOur search yielded 2,361 studies on gestational tissues including placenta, decidua, myometrium, maternal blood, cervix, fetal membranes (chorion and amnion), umbilical cord, fetal blood, and basal plate. Selecting only those original research studies that measured transcription on a genome-wide scale and reported lists of expressed genetic elements identified 93 gene expression, 21 microRNA, and 20 methylation studies. Although 30 % of all PTB cases are due to medical indications, 76 % of the preterm studies focused on them. In contrast, only 18 % of the preterm studies focused on spontaneous onset of labor, which is responsible for 45 % of all PTB cases. Furthermore, only 23 of the 10,993 unique genetic elements reported to be transcriptionally active were recovered 10 or more times in these 134 studies. Meta-analysis of the 93 gene expression studies across 9 distinct gestational tissues and 29 clinical phenotypes showed limited overlap of genes identified as differentially expressed across studies.ConclusionsOverall, profiles of differentially expressed genes were highly heterogeneous both between as well as within clinical subtypes and tissues as well as between studies of the same clinical subtype and tissue. These results suggest that large gaps still exist in the transcriptomic study of specific clinical subtypes as well in the generation of the transcriptional profile of well-studied clinical subtypes; understanding the complex landscape of prematurity will require large-scale, systematic genome-wide analyses of human gestational tissues on both understudied and well-studied subtypes alike.

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Transcriptomics of maternal and fetal membranes can discriminate between gestational-age matched preterm neonates with and without cognitive impairment diagnosed at 18-24 months.

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Transcriptomics of maternal and fetal membranes can discriminate between gestational-age matched preterm neonates with and without cognitive impairment diagnosed at 18-24 months.

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