Analysis of polymorphisms, promoter methylation, and mRNA expression profile of maternal and placental P53 and P21 genes in preeclamptic and normotensive pregnant women

Abstract

BackgroundPreeclampsia (PE), as a multisystem disorder, is associated with maternal hypertension and proteinuria. Apoptosis seems to be involved in the pathophysiology of PE, although its precise pathogenic mechanisms are not well established. In this study, we aimed to identify the association between maternal TP53-rs1042522, P21-rs1801270, and P21-rs1059234 polymorphisms and PE. In addition, we examined the effects of promoter methylation and TP53 and P21 polymorphisms on placental mRNA expression in PE women.MethodsThe blood of 226 PE women and 228 normotensive pregnant women was examined in this study. In addition, the placentas were genotyped in 109 PE and 112 control women. The methylation status was assessed by a methylation-specific PCR assay, while mRNA expression was examined via Quantitative Real Time PCR.ResultsThe maternal and placental P21-rs1801270 CA genotype had a significant association with the reduced risk of PE. In the dominant, recessive, and allelic models, maternal/placental P21-rs1059234 polymorphism had no statistically significant association with the risk of PE. On the other hand, the reduced risk of PE was associated with maternal, but not placental TP53-rs1042522 polymorphism in the dominant and recessive models. The maternal and placental P21-rs1801270 polymorphism was associated with PE risk. The maternal P21 Trs1059234Crs1801270 haplotype was associated with 3.4-fold increase in PE risk, However the maternal P21 Trs1059234Ars 1801270 haplotype and placental Crs1059234CA rs1801270 haplotype led to 0.5 and 0.4-fold decrease in PE risk, respectively. PE women showed 5.6 times higher levels of placental mRNA expression of TP53 gene, although it was not associated with rs1042522 polymorphism. The relative placental mRNA expression of P21 gene was 0.2 in PE women. It was also 2.4 times higher in individuals with rs1801270CA genotype than those with AA genotype. The hyper-methylation of P21 and TP53 genes in the promoter region was associated with a 3.4-fold and 3-fold increase in PE risk, respectively. However, no association was found between P21 and TP53 mRNA expression and promoter methylation.ConclusionIn conclusion, P21-rs1801270 and TP53-rs1042522 polymorphisms were involved in reduced risk of PE. P21-rs1801270 was associated with decreased P21 mRNA expression. The hyper-methylation of P21 and TP53 genes in the promoter region was associated with a higher PE risk.

CCN3 Signaling Is Differently Regulated in Placental Diseases Preeclampsia and Abnormally Invasive Placenta

“…In addition, we revealed that p53 was significantly elevated in early-onset PE placentas. This observation confirms other reports of increased p53 in PE and FGR complications ( 43 , 65 , 68 , 69 ). Since p53 is involved in regulating apoptotic processes ( 70 ), increased p53 may lead to increased apoptosis of trophoblast cells ( 43 ).…”

“…Thus, the down-regulation of p21 is required to induce apoptosis. Similarly, a further in vitro study confirmed that p21 is down-regulated and p53 is up-regulated in trophoblast cells of preeclamptic placentas (68). In contrast to our findings, Cindrova-Davies et al (73) found that p21 was not significantly different between preterm labor and early-onset PE placentas.…”

The effect of TP53 and P21 gene polymorphisms on papillary thyroid carcinoma susceptibility and clinical/pathological features

“…It has been shown that the G allele of rs1042522 in p53 comparing with C allele decreases proapoptotic activity and finally mediates the reduction of the p53 pathway in concert with other p53 targets . To our knowledge, there is no published report regarding to the effect of this polymorphism on gene expression and cancer risk, however, we previously examined the role of rs1042522 on p53 mRNA expression in preeclamptic placentas and found no relationship between this polymorphism and p53 mRNA expression . Although these two amino acids have different properties, despite many studies, there is no exact finding on the role of codon 72 polymorphism in cancer development.…”

“…14 To our knowledge, there is no published report regarding to the effect of this polymorphism on gene expression and cancer risk, however, we previously examined the role of rs1042522 on p53 mRNA expression in preeclamptic placentas and found no relationship between this polymorphism and p53 mRNA expression. 15 Although these two amino acids have different properties, despite many studies, there is no exact finding on the role of codon 72 polymorphism in cancer development. As Wang et al reported the relationship between TP53 rs1042522 polymorphism and thyroid carcinoma in Caucasians but not in Asians.…”

Association between tobacco substance usage and a missense mutation in the tumor suppressor gene P53 in the Saudi Arabian population

“…In addition, in smokers who are also alcoholics, this might contribute to increase susceptibility to the development of carcinoma of the larynx [ 49 ]. Other disruptions in the P53 pathways might result in SNP polymorphisms at the downstream P21, similar to a case in which a P21 polymorphism involving C>A modification at rs1801270 causes the progression of uterine leiomyoma [ 50 ], but decreases the risk of preeclampsia [ 51 ]. Several reports have mentioned that TSU plays an important role in the occurrence of SNP mutations [ 38 , 52 ].…”