OS052. Preeclampsia candidate genes differentially methylated in maternal leukocyte DNA

Altered gene expression in biomarkers associated with preeclampsia/ eclampsia (PE) could be explained in part by epigenetic phenomena such as variable methylation

We sought to characterize the methylation profiles of candidate genes known to be associated with the preeclampsia phenotype in maternal leukocyte DNA in preeclamptic cases and normotensive controls at the time of delivery.

Methylation profiles of maternal leukocyte DNA were evaluated in 14 PE cases and 14 normotensive controls. Subjects were nulliparous, non-smokers, age and BMI matched. Genomic DNA was run on a commercially available beadchip human methylation assay. Mean methylation at sites in genes from a well-defined preeclampsia gene set present on our platform were compared using a t-test.

QC confirmed high correlation of replicates and detection p values >95%. Of the 39 genes in the "preeclampsia gene set", 34 were present on our platform with 73 CpG sites. Seven out of 34 tested in this gene set had differential methylation with p value <0.05. Two genes were found to be less methylated in PE which may result in more expression. AGT (-3%;p= 0.027), angiotensin, is a potent vasoconstrictor with exaggerated effect in PE. DDAH1 (-6%;p=0.031) is involved in nitric oxide generation, via asymmetric dimethylarginine (ADMA), levels of which are known to be altered in PE. Five genes were more methylated and therefore may correlate with reduced transcription. CALCA (+4%;p=0.001) forms calcitonin-gene related peptide, a potent vasodilator decreased in the PE . F5 (+1%;p=0.016), coagulation Factor V, is a target of activated protein C, and increased resistance related to genetic variants (Factor V Leiden) or pregnancy have been associated with PE. MTHFR (+3%;p=0.041) regulates homocysteine; high levels are associated with a 20X increase in risk for PE. POMC (+4%;p=0.014) produces beta endorphin and through ACTH stimulates aldosterone, both decreased in PE. PTGS2 (+3%;p=0.03) is part of the COX 2 prostaglandin pathway involved in inflammation.

Differential methylation of these 7 genes may affect transcription and explain known alterations in gene product associated with PE.