Placenta Thickness Mediates the Association Between AKIP1 Methylation in Maternal Peripheral Blood and Full-Term Small for Gestational Age Neonates

Abstract

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 AKIP1 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 AKIP1 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 AKIP1 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 AKIP1 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 AKIP1 and FT-SGA.

Results: For every increment in standard deviation in the DNAm of CpG4 (cg00061907) at AKIP1, 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 AKIP1 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 AKIP1 in maternal peripheral blood and the risk of FT-SGA, providing new evidence for the mechanism of maternal epigenetics in placental and fetal development.

Keywords: AKIP1; DNA methylation; SGA; mediation effect; placental thickness.

Figure 1

Differences of DNA methylation between groups. β value of DNA methylation distribution across CpGs grouped by FT-AGA and FT-SGA (A). Comparison of the association between DNA methylation levels and FT-SGA across CpGs (B).

Figure 2

The mediation effect of placental thickness on the association of the DNA methylation of CpG4 in AKIP1 and FT-SGA. Models were adjusted for maternal age, education status, marriage status, monthly income, employment, pre-pregnancy body mass index (BMI), conception method, and parity. **: p < 0.01; ***: p < 0.001. OR_TE: odds ratio for total effect. OR_DE: odds ratio for direct effect.