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Xuting Wang¹, Hye-Youn Cho¹, Michelle R Campbell¹

¹Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Building 101, MD C3-03, PO Box 12233, 111 TW Alexander Dr., Research Triangle Park, NC, 27709, USA.

Clinical Epigenetics

|April 28, 2022

Insights

Bronchopulmonary dysplasia (BPD) in premature infants is linked to gestational age and birth weight. Early epigenetic biomarkers, including nucleated red blood cell levels, offer insights into BPD development.

Area of Science:

Neonatal Medicine
Epigenetics
Genomics

Background:

Bronchopulmonary dysplasia (BPD) is a critical lung disease affecting premature infants, often resulting from supplemental oxygen therapy.
Despite advances in neonatal care, BPD incidence is rising, with limited therapeutic interventions for prevention and treatment.
Understanding early risk factors and biomarkers is crucial for improving outcomes in preterm neonates.

Purpose of the Study:

To investigate the association between gestational age, birth weight, and blood cell composition in preterm infants.
To identify early epigenetic biomarkers linked to the development of bronchopulmonary dysplasia (BPD).
To explore the relationship between cord blood methylation profiles and BPD risk.

Main Methods:

Cord blood DNA methylation arrays (Illumina 450K) were used to estimate blood cell-type composition.
Multivariable robust regression identified CpG sites associated with BPD risk.
Epigenome-wide association studies (EWAS) and transcriptome analysis were performed on cord blood samples.

Main Results:

Gestational age and birth weight were significantly associated with BPD development and oxygen supplementation needs.
Nucleated red blood cell (NRBC) percentage showed associations with birth weight, gestational age, and DNA hypomethylation.
EWAS identified numerous differentially methylated CpGs in cord blood linked to BPD, enriched in lung maturation and hematopoiesis pathways.
Elevated stochastic epigenetic mutation burden was observed in infants who developed BPD.

Conclusions:

Nucleated red blood cell content significantly influences DNA methylation profiles in preterm cord blood.
Epigenetic analysis reveals potential biological pathways involved in the pathogenesis of BPD.
Early identification of epigenetic biomarkers may aid in predicting and potentially preventing BPD.

Read full analysis

Abstract

Background:

Bronchopulmonary dysplasia (BPD) is a lung disease in premature infants caused by therapeutic oxygen supplemental and characterized by impaired pulmonary development which persists into later life. While advances in neonatal care have improved survival rates of premature infants, cases of BPD have been increasing with limited therapeutic options for prevention and treatment. This study was designed to explore the relationship between gestational age (GA), birth weight, and estimated blood cell-type composition in premature infants and to elucidate early epigenetic biomarkers associated with BPD.

Methods:

Cord blood DNA from preterm neonates that went on to develop BPD (n = 14) or not (non-BPD, n = 93) was applied to Illumina 450 K methylation arrays. Blood cell-type compositions were estimated using DNA methylation profiles. Multivariable robust regression analysis elucidated CpGs associated with BPD risk. cDNA microarray analysis of cord blood RNA identified differentially expressed genes in neonates who later developed BPD.

Results:

The development of BPD and the need for oxygen supplementation were strongly associated with GA (BPD, p < 1.0E-04; O₂ supplementation, p < 1.0E-09) and birth weight (BPD, p < 1.0E-02; O₂ supplementation, p < 1.0E-07). The estimated nucleated red blood cell (NRBC) percent was negatively associated with birth weight and GA, positively associated with hypomethylation of the tobacco smoke exposure biomarker cg05575921, and high-NRBC blood samples displayed a hypomethylation profile. Epigenome-wide association study (EWAS) identified 38 (Bonferroni) and 275 (false discovery rate 1%) differentially methylated CpGs associated with BPD. BPD-associated CpGs in cord blood were enriched for lung maturation and hematopoiesis pathways. Stochastic epigenetic mutation burden at birth was significantly elevated among those who developed BPD (adjusted p = 0.02). Transcriptome changes in cord blood cells reflected cell cycle, development, and pulmonary disorder events in BPD.

Conclusions:

While results must be interpreted with caution because of the small size of this study, NRBC content strongly impacted DNA methylation profiles in preterm cord blood and EWAS analysis revealed potential insights into biological pathways involved in BPD pathogenesis.

Keywords:

Bronchopulmonary dysplasia Cord blood DNA methylation Epigenome-wide association study Gestational age Lung Nucleated red blood cell Preterm infant Stochastic epimutation cDNA microarray

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