Differential DNA Methylation in Placenta Associated With Maternal Blood Pressure During Pregnancy

Abnormal blood pressure during pregnancy is associated with impaired fetal growth, predisposing the offspring to cardiometabolic abnormalities over the life-course. Placental DNA methylation may be the regulatory pathway through which maternal blood pressure influences fetal and adult health outcomes. Epigenome-wide association study of 301 participants with placenta sample examined associations between DNA methylation and millimetre of mercury increases in systolic and diastolic blood pressure in each trimester. Findings were further examined using gene expression, gene pathway, and functional annotation analyses. Cytosine-(phosphate)-guanine (CpGs) known to be associated with cardiometabolic traits were evaluated. Increased maternal systolic and diastolic blood pressure were associated with methylation of 3 CpGs in the first, 6 CpGs in the second, and 15 CpGs in the third trimester at 5% false discovery rate ( P values ranging from 6.6×10 −15 to 2.3×10 −7 ). Several CpGs were enriched in pathways including cardiovascular-metabolic development ( P =1.0×10 −45 ). Increased systolic and diastolic blood pressure were associated with increased CpG methylation and gene expression at COL12A1 , a collagen family gene known for regulatory functions in the heart. Out of 304 previously reported CpGs known to be associated with cardiometabolic traits, 36 placental CpGs were associated with systolic and diastolic blood pressure in our data. The present study provides the first evidence for associations between placental DNA methylation and increased maternal blood pressure during pregnancy at genes implicated in cardiometabolic diseases. Identification of blood pressure-associated methylated sites in the placenta may provide clues to early origins of cardiometabolic dysfunction and inform guidelines for early prevention. Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00912132.