Associations of long interspersed nuclear element-1 DNA methylation with preterm birth in a prospective cohort study

Abstract

Preterm birth affects over 12% of all infants born in the US yet the biology of early delivery remains unclear, including whether epigenetic mechanisms are involved. We examined associations of maternal and umbilical cord blood long interspersed nuclear element-1 (LINE-1) DNA methylation with length of gestation and odds of preterm birth in singleton pregnancies in Project Viva. In white blood cells from maternal blood during 1st trimester (n=914) and 2nd trimester (n=922), and from venous cord blood at delivery (n=557), we measured LINE-1 by pyrosequencing (expressed as %5 methyl cytosines within the LINE-1 region analyzed [%5mC]). We ran linear regression models to analyze differences in gestation length, and logistic models for odds of preterm birth (<37 v. ≥37 weeks gestation), across quartiles of LINE-1. Mean(SD) LINE-1 levels were 84.3(0.6), 84.5(0.4), and 84.6(0.7) %5mC for 1st trimester, 2nd trimester and cord blood, respectively. Mean(SD) gestational age was 39.5(1.8) weeks, and 6.5% of infants were born preterm. After adjustment for maternal age, race/ethnicity, BMI, education, smoking status, and fetal sex, women with the highest vs. lowest quartile of 1st trimester LINE-1 had longer gestations (0.45 weeks [95% CI 0.12, 0.78]) and lower odds of preterm birth (OR 0.40 [0.17, 0.94]), whereas associations with cord blood LINE-1 were in the opposite direction (−0.45 weeks, −0.83, −0.08) and (OR 4.55 [1.18, 17.5]). In conclusion, higher early pregnancy LINE-1 predicts lower risk of preterm birth. In contrast, preterm birth is associated with lower LINE-1 in cord blood.

Prenatal exposure to mixtures of xenoestrogens and repetitive element DNA methylation changes in human placenta

“…Average correlations of CpG sites within the same repetitive element ranged from 0.15 to 0.76 (Supplemental Material, Table S2) and therefore we decided to use CpG position as a random effect rather than averaging methylation across sites, similarly to what has been suggested by other authors (Burris et al 2012). …”

Prevention of preterm birth: Harnessing science to address the global epidemic

“…Several recent studies have provided molecular evidence for epigenetic effects related to PTB. For example, when researchers analyzed myometrial samples from pregnant women, they found that DNA methylation in regions flanking a subset of contraction-associated genes differed depending on whether the specimen was obtained at term or preterm, and with or without spontaneous labor (23 (25). In contrast, the associations with cord blood LINE-1 methylation were in the opposite direction.…”

Epigenetics: linking social and environmental exposures to preterm birth

“…Whether unique transferable epigenetic marks are set in germ cells after prematurity is only beginning to be studied. Cross-sectional studies of cord blood of preterm neonates reveal distinct DNA methylation profiles from term infants (38,39). Whether these differences would also be present if they fetuses of the same gestation age were compared to the preterm infants has not been studied.…”