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Newborns of obese parents have altered DNA methylation patterns at imprinted genes.

Soubry A, Murphy SK, Wang F, Huang Z, Vidal AC, Fuemmeler BF, Kurtzberg J, Murtha A, Jirtle RL, Schildkraut JM, Hoyo C - Int J Obes (Lond) (2013)

Bottom Line: After adjusting for potential confounders and cluster effects, paternal obesity was significantly associated with lower methylation levels at the MEST (β=-2.57; s.e.=0.95; P=0.008), PEG3 (β=-1.71; s.e.=0.61; P=0.005) and NNAT (β=-3.59; s.e.=1.76; P=0.04) DMRs.We found altered methylation outcomes at multiple imprint regulatory regions in children born to obese parents, compared with children born to non-obese parents.The acquired imprint instability may be carried onto the next generation and increase the risk for chronic diseases in adulthood.

View Article: PubMed Central - PubMed

Affiliation: 1] Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA [2] Epidemiology Research Group, Department of Public Health and Primary Care, Faculty of Medicine, KULeuven, Leuven, Belgium.

ABSTRACT

Background: Several epidemiologic studies have demonstrated associations between periconceptional environmental exposures and health status of the offspring in later life. Although these environmentally related effects have been attributed to epigenetic changes, such as DNA methylation shifts at imprinted genes, little is known about the potential effects of maternal and paternal preconceptional overnutrition or obesity.

Objective: We examined parental preconceptional obesity in relation to DNA methylation profiles at multiple human imprinted genes important in normal growth and development, such as: maternally expressed gene 3 (MEG3), mesoderm-specific transcript (MEST), paternally expressed gene 3 (PEG3), pleiomorphic adenoma gene-like 1 (PLAGL1), epsilon sarcoglycan and paternally expressed gene 10 (SGCE/PEG10) and neuronatin (NNAT).

Methods: We measured methylation percentages at the differentially methylated regions (DMRs) by bisulfite pyrosequencing in DNA extracted from umbilical cord blood leukocytes of 92 newborns. Preconceptional obesity, defined as BMI ⩾30 kg m(-2), was ascertained through standardized questionnaires.

Results: After adjusting for potential confounders and cluster effects, paternal obesity was significantly associated with lower methylation levels at the MEST (β=-2.57; s.e.=0.95; P=0.008), PEG3 (β=-1.71; s.e.=0.61; P=0.005) and NNAT (β=-3.59; s.e.=1.76; P=0.04) DMRs. Changes related to maternal obesity detected at other loci were as follows: β-coefficient was +2.58 (s.e.=1.00; P=0.01) at the PLAGL1 DMR and -3.42 (s.e.=1.69; P=0.04) at the MEG3 DMR.

Conclusion: We found altered methylation outcomes at multiple imprint regulatory regions in children born to obese parents, compared with children born to non-obese parents. In spite of the small sample size, our data suggest a preconceptional influence of parental life-style or overnutrition on the (re)programming of imprint marks during gametogenesis and early development. More specifically, the significant and independent association between paternal obesity and the offspring's methylation status suggests the susceptibility of the developing sperm for environmental insults. The acquired imprint instability may be carried onto the next generation and increase the risk for chronic diseases in adulthood.

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Related in: MedlinePlus

Changes in DNA methylation percentage at the DMRs of imprinted genes by parental obesity. Difference in methylation percentages between children born from obese parents compared with non-obese parents are shown by CpG site for each DMR studied, adjusted for cluster effects. The methylation percentages at baseline, representing the outcome for non-obese parents, are shown in Table 2. Bars represent s.e.
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Figure 1: Changes in DNA methylation percentage at the DMRs of imprinted genes by parental obesity. Difference in methylation percentages between children born from obese parents compared with non-obese parents are shown by CpG site for each DMR studied, adjusted for cluster effects. The methylation percentages at baseline, representing the outcome for non-obese parents, are shown in Table 2. Bars represent s.e.

Mentions: We computed the least square means (or estimated marginal means) of the methylation percentages at each CpG site, accounting for potential effects from multiple laboratory tests on different plates, wells and dates. In order to take into account potential cluster effects, we used mixed models, where well numbers and dates were included as random effects. The methylation outcomes for children born to non-obese parents are presented in Table 2 and were used as a baseline in Figure 1, where differences in methylation percentage by obesity of either of the parents were computed. For further assessment of the effects of maternal and/or paternal obesity on the methylation levels at each DMR we used multivariate procedures, adjusting for potential confounding and accounting for cluster effects from same person and experimental unit, as well as the covariance at the individual CpGs (Table 3). DNA methylation was the dependent variable, and parental obesity (or BMI) and co-variables were included as described above. Potential confounders were selected on the basis of known or observed associations with DNA methylation at these or other loci and with maternal or paternal obesity. A comparison of the different multivariate analyses, with exclusion or inclusion of most of our variables, did not change our results. We further explored the effects of parental obesity by race and repeated the multivariate analyses in Caucasians and African Americans. However, our statistical power calculations indicated that a stratified analysis represents unstable estimates, caused by the small numbers of obese parents by race. All analyses were based on the available laboratory data for each CpG site at the DMRs. Statistical analyses were conducted in SAS v9.3 (SAS Institute Inc., Cary, NC, USA).


Newborns of obese parents have altered DNA methylation patterns at imprinted genes.

Soubry A, Murphy SK, Wang F, Huang Z, Vidal AC, Fuemmeler BF, Kurtzberg J, Murtha A, Jirtle RL, Schildkraut JM, Hoyo C - Int J Obes (Lond) (2013)

Changes in DNA methylation percentage at the DMRs of imprinted genes by parental obesity. Difference in methylation percentages between children born from obese parents compared with non-obese parents are shown by CpG site for each DMR studied, adjusted for cluster effects. The methylation percentages at baseline, representing the outcome for non-obese parents, are shown in Table 2. Bars represent s.e.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4048324&req=5

Figure 1: Changes in DNA methylation percentage at the DMRs of imprinted genes by parental obesity. Difference in methylation percentages between children born from obese parents compared with non-obese parents are shown by CpG site for each DMR studied, adjusted for cluster effects. The methylation percentages at baseline, representing the outcome for non-obese parents, are shown in Table 2. Bars represent s.e.
Mentions: We computed the least square means (or estimated marginal means) of the methylation percentages at each CpG site, accounting for potential effects from multiple laboratory tests on different plates, wells and dates. In order to take into account potential cluster effects, we used mixed models, where well numbers and dates were included as random effects. The methylation outcomes for children born to non-obese parents are presented in Table 2 and were used as a baseline in Figure 1, where differences in methylation percentage by obesity of either of the parents were computed. For further assessment of the effects of maternal and/or paternal obesity on the methylation levels at each DMR we used multivariate procedures, adjusting for potential confounding and accounting for cluster effects from same person and experimental unit, as well as the covariance at the individual CpGs (Table 3). DNA methylation was the dependent variable, and parental obesity (or BMI) and co-variables were included as described above. Potential confounders were selected on the basis of known or observed associations with DNA methylation at these or other loci and with maternal or paternal obesity. A comparison of the different multivariate analyses, with exclusion or inclusion of most of our variables, did not change our results. We further explored the effects of parental obesity by race and repeated the multivariate analyses in Caucasians and African Americans. However, our statistical power calculations indicated that a stratified analysis represents unstable estimates, caused by the small numbers of obese parents by race. All analyses were based on the available laboratory data for each CpG site at the DMRs. Statistical analyses were conducted in SAS v9.3 (SAS Institute Inc., Cary, NC, USA).

Bottom Line: After adjusting for potential confounders and cluster effects, paternal obesity was significantly associated with lower methylation levels at the MEST (β=-2.57; s.e.=0.95; P=0.008), PEG3 (β=-1.71; s.e.=0.61; P=0.005) and NNAT (β=-3.59; s.e.=1.76; P=0.04) DMRs.We found altered methylation outcomes at multiple imprint regulatory regions in children born to obese parents, compared with children born to non-obese parents.The acquired imprint instability may be carried onto the next generation and increase the risk for chronic diseases in adulthood.

View Article: PubMed Central - PubMed

Affiliation: 1] Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA [2] Epidemiology Research Group, Department of Public Health and Primary Care, Faculty of Medicine, KULeuven, Leuven, Belgium.

ABSTRACT

Background: Several epidemiologic studies have demonstrated associations between periconceptional environmental exposures and health status of the offspring in later life. Although these environmentally related effects have been attributed to epigenetic changes, such as DNA methylation shifts at imprinted genes, little is known about the potential effects of maternal and paternal preconceptional overnutrition or obesity.

Objective: We examined parental preconceptional obesity in relation to DNA methylation profiles at multiple human imprinted genes important in normal growth and development, such as: maternally expressed gene 3 (MEG3), mesoderm-specific transcript (MEST), paternally expressed gene 3 (PEG3), pleiomorphic adenoma gene-like 1 (PLAGL1), epsilon sarcoglycan and paternally expressed gene 10 (SGCE/PEG10) and neuronatin (NNAT).

Methods: We measured methylation percentages at the differentially methylated regions (DMRs) by bisulfite pyrosequencing in DNA extracted from umbilical cord blood leukocytes of 92 newborns. Preconceptional obesity, defined as BMI ⩾30 kg m(-2), was ascertained through standardized questionnaires.

Results: After adjusting for potential confounders and cluster effects, paternal obesity was significantly associated with lower methylation levels at the MEST (β=-2.57; s.e.=0.95; P=0.008), PEG3 (β=-1.71; s.e.=0.61; P=0.005) and NNAT (β=-3.59; s.e.=1.76; P=0.04) DMRs. Changes related to maternal obesity detected at other loci were as follows: β-coefficient was +2.58 (s.e.=1.00; P=0.01) at the PLAGL1 DMR and -3.42 (s.e.=1.69; P=0.04) at the MEG3 DMR.

Conclusion: We found altered methylation outcomes at multiple imprint regulatory regions in children born to obese parents, compared with children born to non-obese parents. In spite of the small sample size, our data suggest a preconceptional influence of parental life-style or overnutrition on the (re)programming of imprint marks during gametogenesis and early development. More specifically, the significant and independent association between paternal obesity and the offspring's methylation status suggests the susceptibility of the developing sperm for environmental insults. The acquired imprint instability may be carried onto the next generation and increase the risk for chronic diseases in adulthood.

Show MeSH
Related in: MedlinePlus