Abstract
BackgroundPreterm 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.ResultsThe 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.ConclusionThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1915-4) contains supplementary material, which is available to authorized users.
Highlights
Preterm delivery is the leading cause of neonatal morbidity and mortality
We investigate the genome-wide methylation profile in umbilical cord blood samples (UCB) from 12 preterm and 12 matched term neonates all born after vaginal delivery from normotensive pregnancies and identify genes that could function as leads to establish early diagnostic markers for idiopathic preterm delivery
As an initial check for sample integrity, the 24 samples of the original dataset were grouped as males or females based on their phenotype at birth Multi-dimensional scaling (MDS) analysis was performed on raw intensity signals as a quality control step using the ChAMP package, which resulted in a male neonate born at term (T4) clustering together with the females in our dataset (Fig. 1a)
Summary
Preterm delivery is the leading cause of neonatal morbidity and mortality. Two-thirds of preterm deliveries are idiopathic. 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. 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. Preterm birth, defined as delivery before 37 weeks of gestation, has a global prevalence of 9.6 % It is the leading cause of neonatal morbidity and mortality and is responsible for approximately 70 % of all neonatal deaths and 40 % of childhood neurological morbidities [1, 2]. There are no early diagnostic or prognostic markers for spontaneous preterm birth.
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