Medical morbidities and DNA methylation of NR3C1 in preterm infants

BACKGROUND: Although there are no accepted “normal” levels of circulating cortisol in preterm infants, critically ill preterm infants show lower cortisol levels than healthy preterm infants. The regulation of cortisol reactivity by epigenetic changes in glucocorticoid receptor gene (NR3C1) expression has been demonstrated. This study aims to examine the relationship between medical morbidities in preterm infants and DNA methylation of NR3C1. METHODS: Pyrosequencing was used to determine DNA methylation in CpG sites 1-4 of promoter region 1F of NR3C1. Cluster analysis placed 67 preterm infants born <1,500 g into groups based on medical morbidities. The DNA methylation pattern was compared across groups. RESULTS: Cluster analysis identified a high medical risk cluster and a low medical risk cluster. A Mann-Whitney U-test showed lower methylation at CpG1 for infants in the high-risk group (M = 0.336, SE = 0.084) than infants in the low-risk group (M = 0.617, SE = 0.109, P = 0.032). The false discovery rate was low (q = 0.025). Cohen's D effect size was moderate (0.525). CONCLUSION: Decreased DNA methylation of CpG1 of NR3C1 in high-risk infants may allow for increased binding of transcription factors involved in the stress response, repair and regulation of NR3C1. This may ensure healthy growth in high-risk preterm infants over increasing cortisol levels.