title: Downstream mRNA Target Analysis in Neonatal Hypoxic-Ischaemic Encephalopathy Identifies Novel Marker of Severe Injury: a Proof of Concept Paper.
abstract: 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.
authors.affiliation: Neonatal Brain Research Group, Irish Centre for Fetal and Neonatal Translational Research, Department of Paediatrics and Child Health, Cork University Maternity Hospital, Wilton, Cork, Ireland. am.looney@ucc.ie.
authors.forename: A M
authors.initials: AM
authors.lastname: Looney
authors.affiliation: Neonatal Brain Research Group, Irish Centre for Fetal and Neonatal Translational Research, Department of Paediatrics and Child Health, Cork University Maternity Hospital, Wilton, Cork, Ireland.
authors.forename: C E
authors.initials: CE
authors.lastname: Ahearne
authors.affiliation: Neonatal Department, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Hallberg
authors.affiliation: Neonatal Brain Research Group, Irish Centre for Fetal and Neonatal Translational Research, Department of Paediatrics and Child Health, Cork University Maternity Hospital, Wilton, Cork, Ireland.
authors.forename: G B
authors.initials: GB
authors.lastname: Boylan
authors.affiliation: Neonatal Brain Research Group, Irish Centre for Fetal and Neonatal Translational Research, Department of Paediatrics and Child Health, Cork University Maternity Hospital, Wilton, Cork, Ireland.
authors.forename: D M
authors.initials: DM
authors.lastname: Murray
mesh_terms: D030301:Activin Receptors, Type II / Q000096:biosynthesis* / Q000235:genetics; D028341:Activins / Q000096:biosynthesis / Q000235:genetics; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D018390:Gene Targeting / Q000379:methods*; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000235:genetics / Q000378:metabolism*; D007231:Infant, Newborn; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D000075082:Proof of Concept Study; D012333:RNA, Messenger; D012720:Severity of Illness Index
chemical_list: D005819:Genetic Markers; C587995:MIRN374 microRNA 374, human; D035683:MicroRNAs; D012333:RNA, Messenger; C422405:activin A; D028341:Activins; C579679:ACVR2B protein, human; D030301:Activin Receptors, Type II
keywords: Activin-A; Biomarkers; Hypoxic-ischaemic encephalopathy; MicroRNA; Neuroprotection; miR-374a