The effects of placental long noncoding RNA H19 polymorphisms and promoter methylation on H19 expression in association with preeclampsia susceptibility

Abstract

The effect of DNA methylation on gene expression triggered it as a susceptibility factor in various diseases including preeclampsia (PE). The pathogenesis of PE is closely associated with the methylation status and genetic variants of relevant genes. Therefore, the aim of the study was to investigate the possible impacts of the placental DNA methylation and rs3741219, rs217727, and rs2107425 polymorphisms of the H19 gene on the PE susceptibility as well as the its mRNA expression. Moreover, eight haplotypes of three loci in the H19 gene were analyzed. In this case-control study, the placentas of 107 preeclamptic and 113 non-preeclamptic women were collected after delivery. The methylation status was assessed by methylation-specific polymerase chain reaction (PCR). The H19 polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism or amplification refractory mutation system-polymerase chain reaction methods. The quantitative real time PCR was used for mRNA expression assay. The placental H19 rs3741219 and rs2107425 polymorphisms were not associated with PE. However, H19 rs217727CT and TT genotypes might be associated with a 9.2- and 17.7-fold increased risk of PE, respectively. The T_rs3741219 C_rs217727 C_rs2107425 and T_rs3741219 C_rs217727 T_rs2107425 haplotypes were significantly lower, whereas the T_rs3741219 T_rs217727 C_rs2107425 and C_rs3741219 T_rs217727 C_rs2107425 haplotypes were significantly higher in PE women. Promoter but not upstream region hypermethylation of H19 gene could be led to decreased risk of PE (MM vs. UM + UU). No significant difference was observed in the placental mRNA expression between two groups. The H19 expression was significantly higher in women with unmethylated (UU), compared to methylated promoter (MM). The H19 expression was 17- and 15-fold higher in H19-rs2107425 CC and CT genotypes in PE women. In conclusion, the H19 rs2107425 polymorphism was associated with a higher risk of PE and increased H19 mRNA expression. The promoter hypermethylation of H19 gene was associated with a lower risk of PE and decreased H19 mRNA expression.

Keywords: H19; expression; methylation; placenta; preeclampsia.