Impact of Abnormal DNA Methylation of Imprinted Loci on Human Spontaneous Abortion

Abstract

Currently, there is a growing concern regarding the safety of assisted reproductive technology (ART) due to increased risk of spontaneous abortion (SA) and imprinting disorders in ART-conceived offspring. Early investigations suggested that aberrant genetic imprinting may be related to pregnancy loss; however, few studies have used human tissue specimens. Here the DNA methylation patterns of 3 imprinted genes, including maternally inherited GRB10 and the paternally inherited IGF2 and PEG3 genes, were evaluated in human chorionic villus samples by pyrosequencing and bisulfite sequencing polymerase chain reaction. The samples were divided into 4 groups: (1) SA of natural conception (NC; n = 84), (2) induced abortion of NC (n = 94), (3) SA after ART (n = 73), and (4) fetal reduction after ART (n = 86). The methylation levels and the percentages of abnormal methylation of the IGF2, GRB10, and PEG3 genes between the ART group and the NC group showed no significant difference. Both IGF2 and GRB10 genes showed higher methylation levels in the SA group compared to the non-SA group. Additionally, determining the single-nucleotide polymorphisms of 4 loci, including IGF2 rs3741205, rs3741206, rs3741211, and GRB10 rs2237457, showed that the TC+CC genotype of IGF2 rs3741211 had a 1.91-fold increased risk of SA after ART. However, there was no association between the mutant genotype of IGF2 rs3741211 and the methylation levels of IGF2 and H19, and ART might not affect the distribution of the abovementioned genotypes. It provides support for the opinion that genetic imprinting defects may be associated with SA, which might not be due to ART treatments.

An epigenetic association of malformations, adverse reproductive outcomes, and fetal origins hypothesis related effects

“…There are also links to imprinting disorders [24], with Bincreased prevalence of imprinting defects in patients with Angelman syndrome born to subfertile couples^suggesting a common cause for both [25]. Doornbos et al [26] felt that increases in such disorders with assisted reproduction Bcan fully be explained by the increased fertility problems of the parents.^An imprinted gene polymorphism related to spontaneous abortions with assisted reproduction [27] supports other imprinting effects.…”

Long non‑coding RNA H19 regulates Bcl‑2, Bax and phospholipid hydroperoxide glutathione peroxidase expression in spontaneous abortion

“…During embryonic development, H19 is highly expressed; however, after birth, the expression of H19 is decreased (15). Most studies investigating H19 have focused on its role in carcinogenesis, including tumor growth and metastasis (16,17), and although several studies have analyzed the expression and methylation status of H19 in SA (18,19), whether H19 regulates apoptosis and ferroptosis in SA is unknown.…”

DNA methylation abnormalities of imprinted genes in congenital heart disease: A pilot study

“…Maternal GRB10 knockout results in embryonic overgrowth, and the change of ICR of GRB10 gene results in obvious dysplasia [20,21]. Previous studies have found an increase methylation of GRB10 in fetal samples of spontaneous abortion [22]. It has been found that the Ddc gene in mice, involved in the development of trabecular cardiomyocytes of the embryonic and neonatal heart, displays tight conserved linkage with the methylated GRB10 gene [23].…”