title: The idiopathic preterm delivery methylation profile in umbilical cord blood DNA.
abstract: BACKGROUND
  Preterm delivery is the leading cause of neonatal morbidity and mortality. Two-thirds of preterm deliveries are idiopathic. The initiating molecular mechanisms behind spontaneous preterm delivery are unclear. Umbilical cord blood DNA samples are an easy source of material to study the neonatal state at birth. DNA methylation changes can be exploited as markers to identify spontaneous preterm delivery. To identify methylation differences specific to idiopathic preterm delivery, we assessed genome-wide DNA methylation changes in 24 umbilical cord blood samples (UCB) using the 450 K Illumina methylation array. After quality control, conclusions were based on 11 term and 11 idiopathic preterm born neonates. The differentially methylated positions (DMPs) specific for preterm/term delivery, neonatal sex, use of oxytocin and mode of initiation of labor were calculated by controlling the FDR p value at 0.05.
  
  
  RESULTS
  The analysis identifies 1855 statistically significant DMPs between preterm and term deliveries of which 508 DMPs are also attributable to clinical variables other than preterm versus term delivery. 1347 DMPs are unique to term vs preterm delivery, of which 196 DMPs do not relate to gestational age as such. Pathway analysis indicated enrichment of genes involved in calcium signalling, myometrial contraction and relaxation pathways. The 1151 DMPs that correlate with advancing gestational age (p < 0.05) include 161 DMPs that match with two previously reported studies on UCB methylation. Additionally, 123 neonatal sex specific DMPs, 97 DMPs specific to the induction of labour and 42 DMPs specific to the mode of initiation of labor were also identified.
  
  
  CONCLUSIONS
  This study identifies 196 DMPs in UCB DNA of neonates which do not relate to gestational age or any other clinical variable recorded and are specific to idiopathic preterm delivery. Furthermore, 161 DMPs from our study overlap with previously reported studies of which a subset is also reported to be differentially methylated at 18 years of age. A DMP on MYL4, encoding myosin light chain 4, is a robust candidate for the identification of idiopathic preterm labour as it is identified by all 3 independent studies.
authors.affiliation: Reproductive Biology Laboratory, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. j.f.fernando@amc.uva.nl.
authors.forename: Febilla
authors.initials: F
authors.lastname: Fernando
authors.affiliation: Reproductive Biology Laboratory, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. r.keijser@amc.uva.nl.
authors.forename: Remco
authors.initials: R
authors.lastname: Keijser
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. p.henneman@amc.uva.nl.
authors.forename: Peter
authors.initials: P
authors.lastname: Henneman
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. a.f.vanderkevie-kersemaekers@amc.uva.nl.
authors.forename: Anne-Marie F
authors.initials: AM
authors.lastname: van der Kevie-Kersemaekers
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. m.a.mannens@amc.uva.nl.
authors.forename: Marcel Mam
authors.initials: MM
authors.lastname: Mannens
authors.affiliation: Women's and Children's Clinic, Department of Obstetrics and Gynaecology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. j.a.vanderpost@amc.uva.nl.
authors.forename: Joris Am
authors.initials: JA
authors.lastname: van der Post
authors.affiliation: Reproductive Biology Laboratory, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. g.b.afink@amc.uva.nl.
authors.forename: Gijs B
authors.initials: GB
authors.lastname: Afink
authors.affiliation: Reproductive Biology Laboratory, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. c.ris@amc.uva.nl.|Women's and Children's Clinic, Department of Obstetrics and Gynaecology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. c.ris@amc.uva.nl.
authors.forename: Carrie
authors.initials: C
authors.lastname: Ris-Stalpers
mesh_terms: D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D005312:Fetal Blood; D015894:Genome, Human; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D007752:Obstetric Labor, Premature / Q000235:genetics* / Q000473:pathology; D010121:Oxytocin / Q000235:genetics; D011247:Pregnancy
chemical_list: D010121:Oxytocin