Background: There is cumulating evidence for associations between birthweight-lowering genetic factors and increased risk of type 2 diabetes (T2D). Given the crucial role of the placenta in supporting fetal growth, epigenetic mechanisms in placenta may lend insights into prevention of T2D in early life. We investigated epigenetic changes in placenta associated with birthweight and those that overlap with T2D risk.

Methods: DNA methylation was measured using Illumina’s Infinium Human Methylation450 Beadchip in placenta samples obtained from race/ethnic-diverse pregnant women who participated in the NICHD Fetal Growth Studies (n=301). Associations between DNA methylation and birthweight were tested using linear regression models. Next, we examined whether DNA methylation at loci previously implicated in adult T2D were associated with birthweight in placenta. The relationship between DNA methylation and gene expression was tested in 75 placenta samples profiled for both DNA methylation and gene expression. Statistical tests were considered significant at a false discovery rate < 0.05.

Results: Placenta methylation at 15 cytosine-phosphate-guanine (CpG) sites was significantly associated with birthweight, of which methylation at UBXN11, LBX2, CNIH2, and PDE9A was significantly associated with expression of nearby genes. At six CpG sites (MGRN1, AMIGO2, CHD3 and three intergenic regions) known in previous studies to be associated with adult T2D, we found significant associations between DNA methylation in placenta and birthweight. For all the six CpG sites, the methylation changes related to increased risk of T2D were associated with lower birthweight.

Conclusions: We found novel placental DNA methylation signatures associated with lower birthweight and higher risk of adult T2D. Our findings provide the first evidence to suggest that epigenetic changes in the placenta may be one potential mechanism that explains the link between early growth and later life T2D.

Disclosure

F. Tekola-Ayele: None. T. Workalemahu: None. X. Zeng: None.

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development

© 2020 by the American Diabetes Association
2020
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