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13: Placental CpG methylation varies by extremely preterm birth (PTB) phenotype

      Objective

      Investigations into the genetics of PTB have been difficult to reproduce; more precise phenotype definitions and evaluation of epigenetics may provide additional insight into underlying pathogenesis. We sought to evaluate whether CpG methylation in the placenta differs by PTB phenotype.

      Study Design

      We used placental CpG methylation data from the Extremely Low Gestational Age Newborns study, which included non-anomalous singleton and twin deliveries < 28 weeks’. Placental CpG methylation was interrogated by the Illumina® MethylationEPIC BeadChip; 5,002 CpG sites from 375 PTB candidate genes were evaluated. Women were classified as having ≥1 PTB phenotypes: preeclampsia (PREE), IUGR/fetal indications, SPTB, PPROM, abruption, and cervical insufficiency (CI). Methylation at each CpG site was compared between women with & without each phenotype. Statistical analysis included logistic regression models (controlling a priori for maternal age and race/ethnicity, smoking, and fetal gender) with Bonferroni correction.

      Results

      426 women were included; 23.2% PREE, 34.7% IUGR/fetal indication, 73.2% SPTB, 27.0% PPROM, 45.3% abruption, and 8.5% CI phenotypes. Cohort characteristics are shown in the Table. Methylation of 50 CpG sites within 32 genes was associated with PTB phenotypes (Bonferroni p< 0.05). The most significant differences were observed in IUGR/fetal indication, PREE, and SPTB phenotypes. Notably, even within the same corresponding gene and/or CpG site, methylation was consistently associated with a significantly reduced odds of PTB for fetal indications and PREE but an increased odds of SPTB (Figure). For example, for methylation of cg25406989 and cg255505106 (both in FBN1 gene), the aORs for PREE were 0.43 and 0.40 respectively, but the aORs for SPTB were 1.99 and 2.08 (all p< 0.05). Placental CpG methylation did not differ among those with/without PPROM, abruption, and CI.

      Conclusion

      CpG methylation patterns in placenta-derived DNA differ by PTB indication among extremely low gestational age deliveries. These data may provide additional insight into mechanisms underlying PTB.
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