title: Hypermethylation at loci sensitive to the prenatal environment is associated with increased incidence of myocardial infarction.
abstract: BACKGROUND
  Human epidemiological studies suggest that small size at birth and food deprivation during gestation confer an excess risk of coronary heart diseases (CHD) in adulthood, frequently in a sex-specific manner. Prior epigenetic studies indicate that such prenatal conditions are marked by persistent and sometimes sex-specific changes in DNA methylation. Here, we have investigated the association between DNA methylation and myocardial infarction (MI) at six loci sensitive to prenatal nutrition, anticipating potential sex-specificity. Method Within the placebo group of the PROSPER trial on pravastatin and the risk of CHD, we compared all individuals who were event free at baseline and developed MI during 3 years' follow-up (n = 122) with a similar-sized control group. Methylation at IL10, LEP, ABCA1, IGF2, INS and GNASAS was measured in DNA extracted from leucocytes using mass spectrometry.
  
  
  RESULTS
  DNA methylation at GNASAS was modestly higher in MI cases compared with controls (P = 0.030). A significant sex interaction was observed for INS (P = 0.014) and GNASAS (P = 0.031). Higher DNA methylation at these loci was associated with MI among women (INS: +2.5%, P = 0.002; GNASAS: +4.2%, P = 0.001). Hypermethylation at one locus and at both loci was associated with odds ratios (ORs) of 2.8 and 8.6, respectively (P(trend) = 3.0 × 10(-4)). No association was observed among men.
  
  
  CONCLUSIONS
  The risk of MI in women is associated with DNA methylation marks at specific loci previously shown to be sensitive to prenatal conditions. This observation may reflect a developmental component of MI.
authors.affiliation: Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Rudolf P
authors.initials: RP
authors.lastname: Talens
authors.forename: J W
authors.initials: JW
authors.lastname: Jukema
authors.forename: S
authors.initials: S
authors.lastname: Trompet
authors.forename: D
authors.initials: D
authors.lastname: Kremer
authors.forename: R G J
authors.initials: RG
authors.lastname: Westendorp
authors.forename: L H
authors.initials: LH
authors.lastname: Lumey
authors.forename: N
authors.initials: N
authors.lastname: Sattar
authors.forename: Hein
authors.initials: H
authors.lastname: Putter
authors.forename: P E
authors.initials: PE
authors.lastname: Slagboom
authors.forename: B T
authors.initials: BT
authors.lastname: Heijmans
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D048070:Fetal Nutrition Disorders; D005500:Follow-Up Studies; D059647:Gene-Environment Interaction; D056426:Genetic Loci; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D015994:Incidence; D008297:Male; D009203:Myocardial Infarction / Q000453:epidemiology* / Q000235:genetics* / Q000517:prevention & control; D017035:Pravastatin / Q000627:therapeutic use; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017035:Pravastatin
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