title: DNA methylation profiling of placental villi from karyotypically normal miscarriage and recurrent miscarriage.
abstract: Miscarriage occurs in 15% of clinical pregnancies. Although chromosomal errors are observed in >50%, causes of karyotypically normal losses are poorly understood. DNA methylation undergoes reprogramming during development and must be appropriately set to maintain a healthy pregnancy. We hypothesize that aberrant DNA methylation may cause karyotypically normal miscarriage, particularly among women experiencing recurrent miscarriage (RM). DNA methylation in first-trimester chorionic villi was assessed in chromosomally normal miscarriages from women with RM (N = 33) or isolated miscarriage (M; N = 21) and elective terminations (TA; N = 16). Differentially methylated candidate loci were identified using the Illumina Infinium HumanMethylation27 BeadChip array. Follow-up bisulfite pyrosequencing at promoter regions showed an increase in methylation in M compared with TA at cytochrome P450, subfamily 1A, polypeptide 2 (CYP1A2; P = 0.002) and RM compared with TA at AXL receptor tyrosine kinase (P = 0.02), and a decrease in RM and M compared with TA at defensin β 1 (DEFB1; P = 0.008). Gene ontology analysis showed an enrichment of imprinted genes (P = 9.53 × 10(-10)) and genes previously associated with RM (P = 9.51 × 10(-6)). An increase of outliers at seven imprinted loci was observed in RM (3.9%) compared with M (0%) and TA (0.9%) (P = 0.02), with increased average methylation at H19/IGF2 ICR1 in M samples (P < 0.0001). Altered DNA methylation in the placenta at specific loci, and global dysregulation in specific cases, may contribute to or be a consequence of poor placental function in karyotypically normal miscarriage.
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Courtney W
authors.initials: CW
authors.lastname: Hanna
authors.forename: Deborah E
authors.initials: DE
authors.lastname: McFadden
authors.forename: Wendy P
authors.initials: WP
authors.lastname: Robinson
mesh_terms: D000026:Abortion, Habitual / Q000235:genetics; D000022:Abortion, Spontaneous / Q000235:genetics*; D000328:Adult; D002824:Chorionic Villi / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D020022:Genetic Predisposition to Disease; D018392:Genomic Imprinting; D005865:Gestational Age; D006801:Humans; D059785:Karyotype; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics