Abstract
BackgroundInfants born very preterm are more likely to experience neonatal morbidities compared to their term peers. Variations in DNA methylation (DNAm) associated with these morbidities may yield novel information about the processes impacted by these morbidities.MethodsThis study included 532 infants born < 30 weeks gestation, participating in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants study. We used a neonatal morbidity risk score, which was an additive index of the number of morbidities experienced during the NICU stay, including bronchopulmonary dysplasia (BPD), severe brain injury, serious neonatal infections, and severe retinopathy of prematurity. DNA was collected from buccal cells at discharge from the NICU, and DNAm was measured using the Illumina MethylationEPIC. We tested for differential methylation in association with the neonatal morbidity risk score then tested for differentially methylated regions (DMRs) and overrepresentation of biological pathways.ResultsWe identified ten differentially methylated CpGs (α Bonferroni-adjusted for 706,278 tests) that were associated with increasing neonatal morbidity risk scores at three intergenic regions and at HPS4, SRRD, FGFR1OP, TNS3, TMEM266, LRRC3B, ZNF780A, and TENM2. These mostly followed dose–response patterns, for 8 CpGs increasing DNAm associated with increased numbers of morbidities, while for 2 CpGs the risk score was associated with decreasing DNAm. BPD was the most substantial contributor to differential methylation. We also identified seven potential DMRs and over-representation of genes involved in Wnt signaling; however, these results were not significant after Bonferroni adjustment for multiple testing.ConclusionsNeonatal DNAm, within genes involved in fibroblast growth factor activities, cellular invasion and migration, and neuronal signaling and development, are sensitive to the neonatal health complications of prematurity. We hypothesize that these epigenetic features may be representative of an integrated marker of neonatal health and development and are promising candidates to integrate with clinical information for studying developmental impairments in childhood.
Highlights
Much progress has been made in reducing neonatal morbidity and mortality among infants who are born very preterm (< 30 weeks of gestation)
We examined the relationships between the cumulative impact of serious neonatal morbidities experienced during neonatal intensive care unit (NICU) stay, including bronchopulmonary dysplasia (BPD), severe brain injury (SBI), INF, and severe retinopathy of prematurity (ROP), on DNA methylation (DNAm) measured at NICU discharge; we focus on this set of serious health complications because these are risk factors for persistent impairments later in childhood [1, 3]
While our study focused on epigenetic variation that is associated with the burden of multiple neonatal morbidities in very preterm infants, other studies have previously shown that preterm birth itself is associated with differential DNAm in several different tissues, including placenta [61], neonatal blood [9,10,11], and neonatal saliva [37]
Summary
Much progress has been made in reducing neonatal morbidity and mortality among infants who are born very preterm (< 30 weeks of gestation) These neonates remain at risk for multiple serious medical complications, which often require extended stays in the neonatal intensive care unit (NICU). These include bronchopulmonary dysplasia (BPD), severe brain injury (SBI), severe retinopathy of prematurity (ROP) and serious neonatal infections (INF). The inclusion of neonatal infections and NEC into a cumulative neonatal morbidity risk score, along with BPD, SBI and ROP, improves the ability to predict impairment or death by 18 months of age [3] These severe neonatal morbidities frequently cooccur among premature infants and have some shared risk factors and pathophysiology. Variations in DNA methylation (DNAm) associated with these morbidities may yield novel information about the processes impacted by these morbidities
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