Placental surface area mediates the association between FGFR2 methylation in placenta and full-term low birth weight in girls

Background: Fibroblast growth factor receptor 2 (FGFR2) gene encodes a protein of the fibroblast growth factor receptor family. FGFR2 gene expression is associated with the regulation of implantation process of placenta which plays a vital role in fetal growth. DNA methylation is widely known as a mechanism of fetal growth. However, it is unclear whether and how DNA methylation of FGFR2 gene in the placenta is associated with full-term low birth weight. This case-control study aims to explore the links between FGFR2 methylation in placenta and full-term low birth weight and to further examine the mediation effect of placental surface area on this association. Results: We conducted analyses for each of the five valid CpG sites at FGFR2 in 165 mother-baby pairs (86 FT-LBW vs. 79 FT-NBW) and found that per one standard deviation increase in the DNA methylation of CpG 11 at FGFR2 was associated with 1.64-fold higher risk of full-term low birth weight (OR=1.64, 95% CI=[1.07, 2.52]) and 0.18 standard deviation decrease in placental surface area (β=-0.18; standard error=0.08, p=0.02). The mediation effect of placental surface area on the association between DNA methylation and full-term low birth weight was significant in girls (OR=1.38, 95% CI=[1.05, 1.80]) but not in boys. The estimated mediation proportion was 48.38%. Conclusion: Our findings suggested that placental surface area mediated the association between DNA methylation of FGFR2 in placenta and full-term low birth weight in a sex-specific manner. Our study supported the importance of placental epigenetic changes in placental development and fetal growth.