Serious neonatal morbidities are associated with differences in DNA methylation among very preterm infants

Clinical Epigenetics

Sheri A. DellaGrotta¹  Lynne M. Dansereau¹  Elisabeth C. McGowan²  James F. Padbury²  Barry M. Lester³  Lynne M. Smith⁴  Antoine Soliman⁵  Steven L. Pastyrnak⁶  Charles R. Neal⁷  Julie A. Hofheimer⁸  T. Michael O’Shea⁸  Jennifer Helderman⁹  Brian S. Carter^1,10  Amber Burt^1,11  Carmen J. Marsit^1,11  Todd M. Everson^1,11  Karen Hermetz^1,11 

[1] Brown Center for the Study of Children at Risk, Brown Alpert Medical School and Women and Infants Hospital, Providence, RI, USA;Department of Pediatrics, Brown Alpert Medical School and Women and Infants Hospital, Providence, RI, USA;Department of Pediatrics, Brown Alpert Medical School and Women and Infants Hospital, Providence, RI, USA;Brown Center for the Study of Children at Risk, Brown Alpert Medical School and Women and Infants Hospital, Providence, RI, USA;Department of Psychiatry and Human Behavior, Brown Alpert Medical School, Providence, RI, USA;Department of Pediatrics, Lundquist Institute At Harbor-UCLA Medical Center, Torrance, CA, USA;Department of Pediatrics, Miller Children’s and Women’s Hospital Long Beach, Long Beach, CA, USA;Department of Pediatrics, Spectrum Health-Helen Devos Hospital, Grand Rapids, MI, USA;Department of Pediatrics, University of Hawaii John A. Burns School of Medicine, Honolulu, HI, USA;Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, NC, USA;Department of Pediatrics, Wake Forest School of Medicine, Winston Salem, NC, USA;Department of Pediatrics-Neonatology, Children’s Mercy Hospital, Kansas City, MO, USA;Gangarosa Department of Environmental Health, Emory University Rollins School of Public Health, Atlanta, GA, USA;

关键词: Neonatal;    Preterm;    Methylation;    Epigenetics;    Bronchopulmonary dysplasia;    Brain injury;    Infection;    Retinopathy of prematurity;   

DOI  :  10.1186/s13148-020-00942-1

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY