Preeclampsia (PE), as
multisystem pathological condition that occurs in 3–5% of pregnant women worldwide,
is clinically diagnosed by maternal hypertension and proteinuria 1, 2. Preeclampsia may progress to
eclampsia (convulsive form) due to late presenta­tion, delayed diagnosis, and
delayed treatment; therefore, there is a need to identify reliable hall­marks
for the early diagnosis of preeclampsia and to develop efficient treatment
strategies3.

In spite of
extensive research, the precise pathogenic mechanisms underlying preeclampsia
is still undetermined. However, immune maladaptation, inadequate placental
development and trophoblast invasion, placental ischemia, oxidative stress, and
thrombosis are all thought to represent key factors
in the development of the disease. Furthermore, these components have genetic
factors that may be involved in these pathogenic changes4.

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Proliferation
and apoptosis (programmed cell death) are absolutely necessary components of
the trophoblast life cycle. There are aberrant cell turnover including an
increased apoptosis in placental trophoblast of preeclamptic pregnancies5.

Abnormal
differentiation of cytotrophoblast cells during their invasion of the
spiral uterine
arteries results in a decreased placental size and restricted
utero-placental blood flow, which does not meet the needs of the growing fetus.
As a consequence, hypoxia of the placenta is
followed by an increase in syncytiotrophoblast apoptosis and necrosis6. 

The precise
intracellular mechanisms that promote apoptosis in PE are unknown7. TP53, as a
tumor-suppressor gene, is a key component in cell cycle progression and the
induction of apoptosis8. P53 protein
is an important transcription factor that regulates growth arrest, apoptosis
and DNA repair under cell stress conditions, and then it is phosphorylated and
acetylated at multiple sites to activate downstream target genes9. It was shown
that the level of p53 was increased in placentas during complicated pregnancies;
this finding highlighted the role of P53 in trophoblast apoptosis10. The increased
levels of p53, promotes the downstream transcription of elements involved in
apoptosis and cell-cycle arrest, including p21, a cyclin-dependent kinase
inhibitor7.  

 

The TP53 gene
is located on chromosome 17 and encodes a 53 kDa protein containing 393 amino
acids. The TP53 gene has various single nucleotide polymorphisms (SNPs) with
probable functional effects.  A
well-recognized polymorphism in TP53 gene (P72R, rs1042522) is characterized by
a G>C substitution at codon 72 and is located in the transactivation domain
of the p53 protein that could affect activity of this protein11.

The most
commonly studied polymorphism of p21 gene is serine to arginine replacement in
the codon31 of P21 protein (rs1801270, C98A). This substitution affects the DNA
binding zinc finger motif and may alter expression and activity of p21. Another
p21 polymorphism rs1059234 (C70T) located 20 nucleotides downstream of the stop
codon within the 3’untranslated region. It is considered that, this region is
an important site for cell differentiation, proliferation, and tumor
suppression12.

 

Although several
studies have suggested the importance of the apoptosis pathways and its related
genes in the regulation of PE13, 14; there is no
studies evaluating polymorphisms in P21 gene and correlation with PE
development. In addition, the published reports on the association between P53
gene polymorphisms and PE are sparse in number15. In this
study, we analyzed the frequencies of TP53 (rs1042522, P72R) and P21 (rs1801270,
C98A and rs1059234, C70T) genes polymorphisms and their role as risk factors
for PE development.