Immunity, 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.
Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA.
Clin Epigenetics. 2022 Apr 28;14(1):57. doi: 10.1186/s13148-022-01272-0.
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.
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.
The development of BPD and the need for oxygen supplementation were strongly associated with GA (BPD, p < 1.0E-04; O supplementation, p < 1.0E-09) and birth weight (BPD, p < 1.0E-02; O 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.
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.
支气管肺发育不良（BPD）是一种早产儿的肺部疾病，由治疗性吸氧引起，其特征是肺发育受损，这种情况会持续到生命后期。尽管新生儿护理的进步提高了早产儿的存活率，但 BPD 病例却在增加，而预防和治疗该病的方法有限。本研究旨在探讨早产儿的胎龄（GA）、出生体重和估计的血细胞类型组成之间的关系，并阐明与 BPD 相关的早期表观遗传生物标志物。
对早产儿的脐血 DNA 进行分析，这些早产儿后来发展为 BPD（n=14）或未发展为 BPD（非 BPD，n=93），并应用于 Illumina 450K 甲基化阵列。使用 DNA 甲基化图谱估计血细胞类型组成。多变量稳健回归分析阐明了与 BPD 风险相关的 CpG。对脐血 RNA 的 cDNA 微阵列分析鉴定了后来发展为 BPD 的新生儿中差异表达的基因。
BPD 的发展和对氧气补充的需求与 GA（BPD，p<1.0E-04；O 补充，p<1.0E-09）和出生体重（BPD，p<1.0E-02；O 补充，p<1.0E-07）密切相关。估计的有核红细胞（NRBC）百分比与出生体重和 GA 呈负相关，与烟草烟雾暴露生物标志物 cg05575921 的低甲基化呈正相关，高 NRBC 血样显示低甲基化谱。全基因组关联研究（EWAS）鉴定出 38 个（Bonferroni）和 275 个（错误发现率 1%）与 BPD 相关的差异甲基化 CpG。与 BPD 相关的脐血 CpG 富含肺成熟和造血途径。出生时随机表观遗传突变负担在发展为 BPD 的患者中显著升高（调整后 p=0.02）。BPD 患者的脐带血细胞转录组变化反映了细胞周期、发育和肺部疾病事件。
尽管由于本研究的样本量较小，结果必须谨慎解释，但 NRBC 含量强烈影响早产儿脐带血的 DNA 甲基化谱，EWAS 分析揭示了与 BPD 发病机制相关的生物学途径的潜在见解。
