Downstream mRNA Target Analysis in Neonatal Hypoxic-Ischaemic Encephalopathy Identifies Novel Marker of Severe Injury: a Proof of Concept Paper

• Published in: Molecular neurobiology 2017-12, Vol.54 (10), p.8420-8428
• Main Authors: Looney, A. M., Ahearne, C. E., Hallberg, B., Boylan, G. B., Murray, D. M.
• Format: Article
• Language: English
• Subjects: Activin; Activin Receptors, Type II - biosynthesis; Activin Receptors, Type II - genetics; Activins - biosynthesis; Activins - genetics; Asphyxia; Biomedical and Life Sciences; Biomedicine; Cell Biology; Child, Preschool; Cohort Studies; Cord blood; Encephalopathy; Enzyme-linked immunosorbent assay; Exploration; Female; Follow-Up Studies; Gene Targeting - methods; Genetic Markers - genetics; Humans; Hypoxia; Hypoxia-Ischemia, Brain - genetics; Hypoxia-Ischemia, Brain - metabolism; Infant, Newborn; Infants; Injury analysis; Male; MicroRNAs; MicroRNAs - biosynthesis; MicroRNAs - genetics; miRNA; mRNA; Neonates; Neurobiology; Neurology; Neurosciences; Proof of Concept Study; RNA, Messenger; Severity of Illness Index; Statistical analysis; Umbilical cord
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-016-0330-4

Human microRNA miR-374a is downregulated in the umbilical cord blood (UCB) of infants with hypoxic-ischaemic encephalopathy (HIE). The downstream targets of this microRNA (miRNA) are unclear, but one putative target is the activin-A receptor type IIb (ACVR2B). ACVR2B is required for activin-A function and previous reports have shown alterations of activin-A levels in neonatal HIE. Our aim was to investigate the expression of the potential downstream targets of miR-374a, activin-A and ACVR2B, at birth in a cohort of full-term infants with perinatal asphyxia (PA) only, and those with PA who developed clinical and electrographic HIE. UCB was drawn and processed immediately after delivery. Levels of serum activin-A were measured using ELISA. mRNA levels of ACVR2B in whole blood were quantified using qRT-PCR. Outcome was assessed at 3 years of age using standardised developmental assessment. In total, 171 infants were enrolled: 88 healthy controls, 56 PA and 27 HIE. A statistically significant elevation of median (IQR) ACVR2B was detected in infants with severe HIE compared to moderate/mild HIE, PA and control groups (3.3 (2.94–3.67) vs. 0.91 (0.55–1.21) vs. 0.88 (0.57–1.38) vs. 0.84 (0.74–1.24), p values = 0.04, 0.027 and 0.025, respectively). Although serum activin-A levels were elevated in infants with severe HIE, this elevation did not reach significance. ACVR2B may be a potential novel marker of HIE severity. This is the first study to examine the relationship between activin-A, its receptor AVCR2B and potentially upstream miRNA miR-374a in a cohort of carefully categorised and phenotyped infants. We have shown that miRNA analysis, combined with downstream target exploration, may yield novel biomarkers for the prediction of HIE severity.