Placenta Thickness Mediates the Association Between Methylation in Maternal Peripheral Blood and Full-Term Small for Gestational Age Neonates.

Background/objectives: A-kinase-interacting protein 1 (AKIP1) has been discovered to be a pivotal signaling adaptor in the regulation of human labor and associated with preterm birth, but its effect on fetal growth was still unclear. Meanwhile, the regulation role of DNA methylation (DNAm) on placental and fetal development has been demonstrated. Therefore, we aimed to investigate the association of DNAm in maternal peripheral blood with placental development and full-term small for gestational age (FT-SGA) neonates, and to explore whether placenta mediate the association between DNAm and FT-SGA; Methods: This study was a case-control study including 84 FT-SGAs and 84 FT-AGAs derived from the Shenzhen Birth Cohort Study. The DNA methylation analysis of CpG in the target region of the gene was measured by the Sequenom MassARRAY EpiTYPER approach. Multiple-variable logistic and linear regression analyses were used to estimate the association between the DNAm of three validated CpG sites in the gene, placental thickness, and FT-SGA. Mediation analysis was used to examine the mediation effect of placental development on the association between the DNAm of and FT-SGA.

Results: For every increment in standard deviation in the DNAm of CpG4 (cg00061907) at , the risk of FT-SGA elevated by 2.01-fold (aOR = 2.01, 95%CI = 1.39~3.01), and the thickness of the placenta significantly decreased by a 0.19 standard deviation (β = -0.19, 95%CI = -0.32~ -0.06). Placental thickness mediated the 22.96% of the effect of the DNAm of CpG4 at on the risk of FT-SGA with statistical significance.

Conclusions: The findings in the present study suggested the mediating effect of placental thickness on the association of the DNAm of in maternal peripheral blood and the risk of FT-SGA, providing new evidence for the mechanism of maternal epigenetics in placental and fetal development.