Genomic biomarkers of prenatal intrauterine inflammation in umbilical cord tissue predict later life neurological outcomes

Preterm birth is a major risk factor for neurodevelopmental delays and disorders. This study aimed to identify genomic biomarkers of intrauterine inflammation in umbilical cord tissue in preterm neonates that predict cognitive impairment at 10 years of age

Placental CpG methylation of infants born extremely preterm predicts cognitive impairment later in life

Abstract: Background The placenta is the central regulator of maternal and fetal interactions. Perturbations of placental structure and function have been associated with adverse neurodevelopmental outcomes later in life. Placental CpG methylation represents an epigenetic modification with the potential to impact placental function, fetal development and child health later in life. Study design Genome-wide placental CpG methylation levels were compared between spontaneous versus indicated deliveries from extremely preterm births (EPTBs) (n = 84). The association between the identified differentially methylated CpG sites and neurocognitive outcome at ten years of age was then evaluated. Results Spontaneous EPTB was associated with differential CpG methylation levels in 250 CpG sites (217 unique genes) with the majority displaying hypermethylation. The identified genes are known to play a role in neurodevelopment and are enriched for basic helix-loop-helix transcription factor binding sites. The placental CpG methylation levels for 17 of these sites predicted cognitive function at ten years of age. Conclusion A hypermethylation signature is present in DNA from placentas in infants with spontaneous EPTB. CpG methylation levels of critical neurodevelopment genes in the placenta predicted..

Genomic biomarkers of prenatal intrauterine inflammation in umbilical cord tissue predict later life neurological outcomes

<div><p>Background</p><p>Preterm birth is a major risk factor for neurodevelopmental delays and disorders. This study aimed to identify genomic biomarkers of intrauterine inflammation in umbilical cord tissue in preterm neonates that predict cognitive impairment at 10 years of age.</p><p>Study design</p><p>Genome-wide messenger RNA (mRNA) levels from umbilical cord tissue were obtained from 43 neonates born before 28 weeks of gestation. Genes that were differentially expressed across four indicators of intrauterine inflammation were identified and their functions examined. Exact logistic regression was used to test whether expression levels in umbilical cord tissue predicted neurocognitive function at 10 years of age.</p><p>Results</p><p>Placental indicators of inflammation were associated with changes in the mRNA expression of 445 genes in umbilical cord tissue. Transcripts with decreased expression showed significant enrichment for biological signaling processes related to neuronal development and growth. The altered expression of six genes was found to predict neurocognitive impairment when children were 10 years old These genes include two that encode for proteins involved in neuronal development.</p><p>Conclusion</p><p>Prenatal intrauterine inflammation is associated with altered gene expression in umbilical cord tissue. A set of six of the differentially expressed genes predict cognitive impairment later in life, suggesting that the fetal environment is associated with significant adverse effects on neurodevelopment that persist into later childhood.</p></div

Placental CpG methylation of infants born extremely preterm predicts cognitive impairment later in life - Fig 1

<p>(a) Heatmap of 250 DMPs between placentas from indicated EPTB (n = 25) and spontaneous EPTB (n = 59). Beta-values were mean standardized and red indicates increased methylation levels, while blue indicates decreased methylation levels. Significance was defined as FDR q-value < 0.05 and an absolute beta difference ≥ |0.10|. (b) Intragene probe site distribution for all annotated probes (n = 286,410) contained on the Illumina HumanMethylation450 BeadChip. (c) Intragene probe site distribution for 250 DMPs between placentas from indicated EPTB (n = 25) and spontaneous EPTB (n = 59). The distribution of DMPs associated with intrauterine inflammation contained more probes located within the body region of genes and less probes located within the TSS200 region of genes than would be expected from a random sample of the total probe distribution, as indicated (*).</p

Expression levels of six genes predict neurocognitive outcome at 10 years of age.

<p>Increased levels (red) of two genes that were associated with a maker of intrauterine inflammation predicted more severe neurocognitive at 10 years of age. Decreased levels (blue) of 4 genes that were associated with a maker of intrauterine inflammation predicted more severe neurocognitive at 10 years of age. Significance was defined as an exact p-value < 0.05 in a logistic regression model.</p

Top canonical pathways and protein domains enriched among the 445 genes associated with intrauterine inflammation markers.

<p>Top canonical pathways and protein domains enriched among the 445 genes associated with intrauterine inflammation markers.</p

Heatmap of 445 genes that displayed significant differential expression values across one or more markers of intrauterine inflammation in n = 43 subjects.

<p>The absolute fold change (cases/controls) is displayed for each gene significantly associated with each marker of intrauterine inflammation. Red indicates increased expression in association with a marker of intrauterine inflammation and blue indicates decreased expression in association with a marker of intrauterine inflammation. Rows (genes) were organized by unsupervised hierarchical clustering Euclidean dissimilarity with average linkage. Significance was defined as FDR q-value < 0.05 and fold change ≥ |2.0|.</p

Placental CpG methylation of infants born extremely preterm predicts cognitive impairment later in life

<div><p>Background</p><p>The placenta is the central regulator of maternal and fetal interactions. Perturbations of placental structure and function have been associated with adverse neurodevelopmental outcomes later in life. Placental CpG methylation represents an epigenetic modification with the potential to impact placental function, fetal development and child health later in life.</p><p>Study design</p><p>Genome-wide placental CpG methylation levels were compared between spontaneous versus indicated deliveries from extremely preterm births (EPTBs) (n = 84). The association between the identified differentially methylated CpG sites and neurocognitive outcome at ten years of age was then evaluated.</p><p>Results</p><p>Spontaneous EPTB was associated with differential CpG methylation levels in 250 CpG sites (217 unique genes) with the majority displaying hypermethylation. The identified genes are known to play a role in neurodevelopment and are enriched for basic helix-loop-helix transcription factor binding sites. The placental CpG methylation levels for 17 of these sites predicted cognitive function at ten years of age.</p><p>Conclusion</p><p>A hypermethylation signature is present in DNA from placentas in infants with spontaneous EPTB. CpG methylation levels of critical neurodevelopment genes in the placenta predicted later life cognitive function, supporting the developmental origins of health and disease hypothesis (DOHaD).</p></div

A total of 17 probe sites where increased placental CpG methylation predicted more severe cognitive impairment at ten years of age.

<p>These sites corresponded to 16 unique genes. The model represents the increase in the odds of moderate or severe cognitive impairment at age ten for every one percent increase in methylation at the probe site. Significance was defined as a p-value < 0.05 in a logistic regression model.</p

Enriched canonical pathways among the 217 DMP-associated genes.

<p>Enriched canonical pathways among the 217 DMP-associated genes.</p