title: Fetal DNA methylation of autism spectrum disorders candidate genes: association with spontaneous preterm birth.
abstract: OBJECTIVE
  Autism spectrum disorder (ASD) is associated with preterm birth (PTB), although the reason underlying this relationship is still unclear. Our objective was to examine DNA methylation patterns of 4 ASD candidate genes in human fetal membranes from spontaneous PTB and uncomplicated term birth.
  
  
  METHODS
  A literature search for genes that have been implicated in ASD yielded 14 candidate genes (OXTR, SHANK3, BCL2, RORA, EN2, RELN, MECP2, AUTS2, NLGN3, NRXN1, SLC6A4, UBE3A, GABA, AFF2) that were epigenetically modified in relation to ASD. DNA methylation in fetal leukocyte DNA in 4 of these genes (OXTR, SHANK3, BCL2, and RORA) was associated with PTB in a previous study. This study evaluated DNA methylation, transcription (reverse transcription polymerase chain reaction), and translation patterns (immunostaining and Western blot) in fetal membrane from term labor (n = 14), term not in labor (TNIL; n = 29), and spontaneous preterm birth (PTB; n = 27). Statistical analysis was performed with analysis of variance; a probability value of < .05 was significant.
  
  
  RESULTS
  Higher methylation of the OXTR promoter was seen in fetal membranes from PTB, compared with term labor or TNIL. No other gene showed any methylation differences among groups. Expression of OXTR was not different among groups, but the 70 kDa OXTR protein was seen only in PTB, and immunostaining was more intense in PTB amniocytes than term labor or TNIL.
  
  
  CONCLUSIONS
  Among the 4 genes that were studied, fetal membranes from PTB demonstrate differences in OXTR methylation and regulation and expression, which suggest that epigenetic alteration of this gene in fetal membrane may likely be indicating an in utero programing of this gene and serve as a surrogate in a subset of PTB. The usefulness of OXTR hypermethylation as a surrogate for a link to ASD should be further evaluated in longitudinal and in vitro studies.
authors: Division of Maternal-Fetal Medicine and Perinatal Research, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX.
authors: Fara
authors: F
authors: Behnia
authors: Genetics and Molecular Biology Program, Emory University School of Medicine, Atlanta, GA.
authors: Sasha E
authors: SE
authors: Parets
authors: Division of Maternal-Fetal Medicine and Perinatal Research, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX.
authors: Talar
authors: T
authors: Kechichian
authors: Division of Maternal-Fetal Medicine and Perinatal Research, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX.
authors: Huaizhi
authors: H
authors: Yin
authors: Division of Maternal-Fetal Medicine and Perinatal Research, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX.
authors: Eryn H
authors: EH
authors: Dutta
authors: Division of Maternal-Fetal Medicine and Perinatal Research, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX.
authors: George R
authors: GR
authors: Saade
authors: Genetics and Molecular Biology Program, Emory University School of Medicine, Atlanta, GA; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA.
authors: Alicia K
authors: AK
authors: Smith
authors: Division of Maternal-Fetal Medicine and Perinatal Research, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX. Electronic address: ra2menon@utmb.edu.
authors: Ramkumar
authors: R
authors: Menon
mesh_terms: D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D016022:Case-Control Studies; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005321:Extraembryonic Membranes; D005260:Female; D005819:Genetic Markers; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics; D011247:Pregnancy; D047928:Premature Birth / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D018045:Receptors, Oxytocin / Q000235:genetics*; D000091042:Reelin Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047929:Term Birth / Q000235:genetics; D055815:Young Adult
chemical_list: C000595707:BCL2 protein, human; D005819:Genetic Markers; D009419:Nerve Tissue Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C569600:OXTR protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; C539738:RORA protein, human; D018045:Receptors, Oxytocin; D000091042:Reelin Protein; C492357:SHANK3 protein, human; C000717127:RELN protein, human
keywords: OXTR; epigenetics; hydroxymethylation; programing