Association between length of gestation and cervical DNA methylation of PTGER2 and LINE 1-HS

Abstract

Worldwide, more than 1 in 10 infants is born prior to 37 weeks gestation. Preterm birth can lead to increased mortality risk and poor life-long health and neurodevelopmental outcomes. Whether environmental risk factors affect preterm birth through epigenetic phenomena is largely unstudied. We sought to determine whether preterm risk factors, such as smoke exposure and education, were associated with cervical DNA methylation in the prostaglandin E receptor 2 gene (PTGER2) and a repetitive element, long interspersed nuclear element-1 Homo sapiens-specific (LINE 1-HS). Second, we aimed to determine whether mid-pregnancy DNA methylation of these regions in cervical samples could predict the length of gestation. We obtained a cervical swab between 16-19 weeks gestation from 80 women participating in a Mexico City birth cohort, used pyrosequencing to analyze DNA methylation of PTGER2 and LINE 1-HS, and examined associations with maternal covariates. We used accelerated failure time models to analyze associations of DNA methylation with the length of gestation. DNA methylation of both sequences was associated with Pap smear inflammation. LINE 1-HS methylation was associated with smoke exposure, BMI and parity. In adjusted models, gestations were 3.3 days longer (95%CI 0.6, 6.0) for each interquartile range of PTGER2 DNA methylation. Higher LINE 1-HS methylation was associated with shorter gestations (-3.3 days, 95%CI -6.5, -0.2). In conclusion, cervical DNA methylation was associated with risk factors for preterm birth and the length of gestation.

Keywords: Cervix; DNA methylation; LINE 1; PTGER2; Preterm birth; epigenetics.

Figure 1. Cervical prostaglandin E receptor 2 (subtype EP2) (PTGER2) DNA methylation and gestational age (days), ELEMENT birth cohort, Mexico City (n = 73).

Figure 2. Cervical long interspersed nuclear element-1 Homo sapiens specific (LINE 1-HS) DNA methylation and gestational age (days), ELEMENT birth cohort, Mexico City (n = 74).

Figure 3. Gestational Age Differences per interquartile range of cervical DNA methylation of PTGER2 and LINE 1-HS, ELEMENT birth cohort, Mexico City. Model 1: Unadjusted Model 2: Adjusted for maternal age Model 3: Model 2 additionally adjusted for Pap smear inflammation Abbreviations: PTGER2 prostaglandin E receptor 2 (subtype EP2); LINE 1-HS long interspersed nuclear element-1 Homo sapiens-specific. Footnote: n = 69 for PTGER2 models and n = 71 for LINE 1-HS models; error bars indicate 95% confidence intervals.