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Epigenome-wide DNA methylation in maternal blood and preterm birth (PTB)

      Objective

      PTB is a multifactorial condition with poorly understood pathophysiology and challenges in prediction. Epigenetics may provide additional insight into the underlying pathogenesis. We sought to evaluate whether CpG methylation in maternal blood differs among those delivering preterm.

      Study Design

      Planned primary analysis of a prospective observational cohort study that recruited patients at a single, tertiary University-based hospital carrying singleton, non-anomalous gestations who were at high risk for spontaneous PTB due to a high-risk obstetric history or current pregnancy complication. Placental CpG methylation at ∼850,000 CpG sites genome wide in maternal blood was interrogated by the Illumina® MethylationEPIC BeadChip. The primary outcome was PTB < 37 weeks’ gestation. Secondary outcomes were PTB < 34 and < 28 weeks’ gestation. We compared CpG methylation at each gestational age cutoff. Statistical analysis included logistic regression models (controlling a priori for maternal age, insurance status, smoking, male fetal sex, and gestational age at blood sampling) with Bonferroni correction. A q-value < 0.10 was considered statistically significant.

      Results

      180 patients met inclusion criteria; 53% delivered < 37 weeks. Cohort characteristics are shown in Table 1. Most women (167/180, 93%) had their blood drawn for DNA methylation analysis prior to 28 weeks’ gestation. Methylation of 3 CpG sites within 3 genes was associated with PTB < 37 weeks’ gestation (Table 2). Two additional CpG sites were identified for those patients delivering < 34 and < 28 weeks’ gestation. Of the 5 identified differentially methylated genes, 2 have been previously associated with PTB or related conditions (SASH3, CYTH2), whereas there are no previously published reports identifying an association between the other 3 (NXT1, PRRT3, SIL1) and PTB or pregnancy complications.

      Conclusion

      We identified 5 CpG sites in 5 different genes with differential methylation in maternal blood among patients delivering preterm vs. term. These data may provide additional insight into mechanisms underlying PTB.
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