Human Molecular Genetics Advance Access originally published online on August 4, 2009
Human Molecular Genetics 2009 18(21):4046-4053; doi:10.1093/hmg/ddp353
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DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific
1 Molecular Epidemiology 2 Medical Statistics 3 Endocrinology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands 4 Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA 5 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
* To whom correspondence should be addressed at: Molecular Epidemiology Section, Leiden University Medical Center, Postal Zone S-05-P, PO Box 9600, 2300 RC Leiden, The Netherlands. Tel: +31 715269785; Fax: +31 715268280; Email: b.t.heijmans{at}lumc.nl
Received June 8, 2009; Revised July 10, 2009; Accepted July 26, 2009
Prenatal famine in humans has been associated with various later-life consequences, depending on the gestational timing of the insult and the sex of the exposed individual. Epigenetic mechanisms have been proposed to underlie these associations. Indeed, animal studies and our early human data on the imprinted IGF2 locus indicated a link between prenatal nutritional and DNA methylation. However, it remains unclear how common changes in DNA methylation are and whether they are sex- and timing-specific paralleling the later-life consequences of prenatal famine exposure. To this end, we investigated the methylation of 15 loci implicated in growth and metabolic disease in individuals who were prenatally exposed to a war-time famine in 1944–45. Methylation of INSIGF was lower among individuals who were periconceptionally exposed to the famine (n = 60) compared with their unexposed same-sex siblings (P = 2 x 10–5), whereas methylation of IL10, LEP, ABCA1, GNASAS and MEG3 was higher (all P < 10–3). A significant interaction with sex was observed for INSIGF, LEP and GNASAS. Next, methylation of eight representative loci was compared between 62 individuals exposed late in gestation and their unexposed siblings. Methylation was different for GNASAS (P = 1.1 x 10–7) and, in men, LEP (P = 0.017). Our data indicate that persistent changes in DNA methylation may be a common consequence of prenatal famine exposure and that these changes depend on the sex of the exposed individual and the gestational timing of the exposure.