Placental DNA methylation at term reflects maternal serum levels of INHA and FN1, but not PAPPA, early in pregnancy

Samantha L. Wilson, John D. Blair, Kirsten Hogg, Sylvie Langlois, Peter von Dadelszen, Wendy P. Robinson

Early detection of pregnancies at risk of complications, such as intrauterine growth restriction (IUGR) and preeclampsia (PE), is critical for improved monitoring and preventative treatment to optimize health outcomes. We predict that levels of placental-derived proteins circulating in maternal blood reflect placental gene expression, which is associated with placental DNA methylation (DNAm) profiles. As such, placental DNAm profiling may be useful to distinguish pregnancies at risk of developing complications and correlation between DNAm and protein levels in maternal blood may give further evidence for a protein's use as a biomarker. However, few studies investigate all clinical parameters that may influence DNAm and/or protein expression, which can significantly affect the relationship between these measures. Candidate genes were chosen based on i) reported alterations of protein levels in maternal blood and ii) observed changes in placental DNAm (∆β > 0.05 and False Discovery Rate (FDR) <0.05) in pregnancies complicated by PE/IUGR. Fibronectin (FN1) enhancer DNAm and placental gene expression were inversely correlated (r = -0.88 p < 0.01). The same trend was observed between promoter DNAm and gene expression for INHBA and PAPPA, though not significant. INHBA and FN1 DNAm was associated with gestational-age corrected birth weight, while INHA levels were associated with fetal: placental weight ratio and FN1 level was associated with maternal body mass index (BMI). DNAm at the INHBA promoter in the term placenta was negatively correlated with second trimester maternal serum levels (r = -0.50 p = 0.01) and DNAm at the FN1 enhancer was negatively associated with third trimester maternal serum levels (r = -0.38, p = 0.009). However, a similar correlation was not found for PAPPA. These results show that establishing a correlation between altered DNAm in the term placenta and altered maternal serum levels of the corresponding protein, is affected by a number of factors. Nonetheless, the correlation between placental DNAm of INHBA/FN1 and maternal serum INHA/FN1 levels indicate that DNAm may be a useful tool to identify novel biomarkers for adverse pregnancy outcomes in some cases.