MicroRNA Expression Aberration Associated with Bronchopulmonary Dysplasia in Preterm Infants: A Preliminary Study

Abstract

BACKGROUND: Because environmental insults and genetic factors account for the variance in the risk of bronchopulmonary dysplasia (BPD) in very low birth weight (VLBW, birth weight < 1,500 g) preterm infants, the search for BPD biomarkers has begun to focus on the regulators of non-coding RNA such as microRNAs (miRNAs). Therefore, this study aimed to identify potential miRNAs involved in the pathogenesis of BPD in VLBW preterm infants. METHODS: A case-control study (15 subjects with BPD and 15 sex-matched control subjects without BPD) was conducted to investigate the expression profiles of 365 miRNAs in the peripheral blood of VLBW preterm infants at 36 weeks post-menstrual age (called the older-age set). The expression levels of identified miRNAs were further evaluated in a subsample of blood collected during the first 2 weeks post-natal age (called the younger-age set). Possible biological functions and pathways implicated in the target genes regulated by the miRNAs were explored using database predictions. RESULTS: A 4-miRNA signature (miR-152, miR-30a-3p, miR-133b, and miR-7) with aberrant expression levels at 36 weeks, derived from a supervised classification with internal cross-validation, discriminated the subjects with BPD from those without BPD with an accuracy of 0.91. The discriminative accuracy of the 4 miRNAs was supported by random permutations of either the disease status or the number of miRNAs selected (both P < .001). A down-regulation change of miR-152 and miR-30a-3p expression levels and an up-regulation change of miR-133b and miR-7 expression levels were found in the older-age set, compared to the younger-age set. CONCLUSIONS: This is the first study to identify blood-based miRNAs associated with BPD. The findings provide information regarding the roles of these biomarkers in the development of BPD in VLBW preterm infants.

Modulated expression of human peripheral blood microRNAs from infancy to adulthood and its role in aging

“…There are only limited existing data to evaluate the impact of including such heterogeneous subgroups of participants in the analysis on the findings. For example, among the 23 miRNAs with age-limited expression and 101 differentially expressed miRNAs, one (miR-652) was up-regulated in schizophrenia (Lai et al ., 2011), and three others were either down-regulated (miR-152) or up-regulated (miR-133b and miR-7) in bronchopulmonary dysplasia (Wu et al ., 2013), all in peripheral blood. Meanwhile, among the 101 differentially expressed miRNAs, 12 (Tables S4 and S5) were found to be down-regulated in the postmortem brain tissue of patients with schizophrenia (Gardiner et al ., 2012).…”

“…The screening set consisted of preterm infants ( n = 30, mean gestational age = 29.1 weeks) and adults ( n = 60, mean age = 37 years), and the validation set consisted of independent samples of preterm infants ( n = 22, mean gestational age = 28.9 weeks), children ( n = 66, mean age = 9.1 years), and adults ( n = 68, mean age = 36.9 years). For the preterm infants, we enrolled very-low-birth-weight preterm infants who were admitted to the neonatal intensive care unit at the National Taiwan University Hospital and Mackey Memorial Hospital in Taipei, Taiwan, from September 2008 to December 2009, as described in more detail in a previous study (Wu et al ., 2013). Briefly, the inclusion criteria included gestational age ≤ 33 weeks, birth weight < 1500 g, absence of congenital and chromosomal abnormalities, and infants who were born in or admitted to the neonatal intensive care unit within 7 days of birth.…”

Impaired Pulmonary Vascular Development in Bronchopulmonary Dysplasia

“…In both mice and human lung tissues, DNA methylation, another form of epigenetic regulation, has been shown to alter expression of genes associated with lung development and alveolar septation including a number of genes in angiogenic pathways [75]. Several studies have also shown that epigenetic regulation by microRNA expression is aberrant in BPD [76, 77]. Transgenic miR-150 knockout mice demonstrate increased angiogenesis when exposed to neonatal hyperoxia that may be due to upregulation of glycoprotein non-metastatic melanoma protein B (GPNMB) [78].…”

Epigenetic contributions to the developmental origins of adult lung disease

“…One study reported expression profiles of miRNA in peripheral blood of late-preterm infants with and without BPD (Wu et al, 2013). A 4-miRNA signature was identified as characterizing preterm infants with BPD.…”

“…A 4-miRNA signature was identified as characterizing preterm infants with BPD. The miRNAs that differed in magnitude between preterm infants with BPD and those without were miR-152, miR-30a-3p, miR-133b, and miR-7 (Wu et al, 2013). The presence of a miRNA signature in peripheral blood that might serve as a biomarker is an exciting prospect.…”