DNA Methylation Profiling of Placental Villi From Karyotypically Normal Miscarriage and Recurrent Miscarriage

Am J Pathol. 2013 Jun;182(6):2276-84. doi: 10.1016/j.ajpath.2013.02.021. Epub 2013 Apr 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abortion, Habitual / genetics
  • Abortion, Spontaneous / genetics*
  • Adult
  • Chorionic Villi / metabolism*
  • DNA Methylation*
  • Female
  • Genetic Predisposition to Disease
  • Genomic Imprinting
  • Gestational Age
  • Humans
  • Karyotype
  • Pregnancy
  • Promoter Regions, Genetic / genetics