title: Placental DNA methylation at term reflects maternal serum levels of INHA and FN1, but not PAPPA, early in pregnancy.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Child & Family Research Institute, 950 W 28th Ave, Vancouver, BC, V5Z 4H4, Canada. swils6@alumni.ubc.ca.|Department of Medical Genetics, University of British Columbia, C201-4500 Oak St, Vancouver, BC, V6H3N1, Canada. swils6@alumni.ubc.ca.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Wilson
authors.affiliation: Child & Family Research Institute, 950 W 28th Ave, Vancouver, BC, V5Z 4H4, Canada. jblair@berkeley.edu.|Department of Medical Genetics, University of British Columbia, C201-4500 Oak St, Vancouver, BC, V6H3N1, Canada. jblair@berkeley.edu.|Department of Molecular & Cell Biology, University of California Berkeley, Berkeley, CA, USA. jblair@berkeley.edu.
authors.forename: John D
authors.initials: JD
authors.lastname: Blair
authors.affiliation: Child & Family Research Institute, 950 W 28th Ave, Vancouver, BC, V5Z 4H4, Canada. kirsten.hogg@hudson.org.au.|Hudson Institute of Medical Research, Centre for Genetic Diseases, 27-31 Wright Street, Melbourne, Australia. kirsten.hogg@hudson.org.au.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hogg
authors.affiliation: Child & Family Research Institute, 950 W 28th Ave, Vancouver, BC, V5Z 4H4, Canada. slanglois@cw.bc.ca.|Department of Medical Genetics, University of British Columbia, C201-4500 Oak St, Vancouver, BC, V6H3N1, Canada. slanglois@cw.bc.ca.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Langlois
authors.affiliation: Child & Family Research Institute, 950 W 28th Ave, Vancouver, BC, V5Z 4H4, Canada. pvd@sgul.ac.uk.|Department of Obstetrics and Gynaecology, University of British Columbia, 4500 Oak St, Vancouver, BC, V6H 3 V5, Canada. pvd@sgul.ac.uk.
authors.forename: Peter
authors.initials: P
authors.lastname: von Dadelszen
authors.affiliation: Child & Family Research Institute, 950 W 28th Ave, Vancouver, BC, V5Z 4H4, Canada. wrobinson@cfri.ca.|Department of Medical Genetics, University of British Columbia, C201-4500 Oak St, Vancouver, BC, V6H3N1, Canada. wrobinson@cfri.ca.
authors.forename: Wendy P
authors.initials: WP
authors.lastname: Robinson
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D019175:DNA Methylation; D042241:Early Diagnosis; D005260:Female; D005317:Fetal Growth Retardation / Q000175:diagnosis / Q000235:genetics; D005353:Fibronectins / Q000097:blood*; D006801:Humans; D007231:Infant, Newborn; D007265:Inhibins / Q000097:blood*; D008297:Male; D010920:Placenta / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000175:diagnosis / Q000235:genetics; D011247:Pregnancy; D011256:Pregnancy Outcome / Q000235:genetics; D011262:Pregnancy Trimester, Second / Q000097:blood*; D011266:Pregnancy-Associated Plasma Protein-A / Q000378:metabolism; D011296:Prenatal Diagnosis; D047929:Term Birth / Q000235:genetics / Q000378:metabolism
chemical_list: C067625:FN1 protein, human; D005353:Fibronectins; C094377:inhibin-alpha subunit; D007265:Inhibins; D011266:Pregnancy-Associated Plasma Protein-A