ANXA5 AND VEGFA GENE VARIANTS
IN WOMEN WITH EARLY PREGNANCY LOSSES
FROM NORTH MACEDONIA
Terzikj M, Bozhinovski Gj, Branoski A, Dimkovska M, Kubelka-Sabit K, Plaseska-Karanfilska D
*Corresponding Author: Corresponding author, Prof. Dijana Plaseska-Karanfilska, MD, PhD.
Research Centre for Genetic Engineering and Biotechnology “Georgi D. Efremov”,
Macedonian Academy of Science and Arts, Skopje, North Macedonia, e-mail: dijana@manu.edu.mk
page: 5
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INTRODUCTION
Early pregnancy loss (EPL), defined as a loss of the
conceptus before the 12th week of gestation, is the most
common pregnancy complication and is found in approxi-
mately 15% of all clinically recognized pregnancies [1].
About 5% of the couples trying for childbirth, experience
recurrent pregnancy loss (RPL), a condition defined as two
or more consecutive pregnancy losses, according to the
European Society of Human Reproduction and Embryol-
ogy (ESHRE) and American Society for Reproductive
Medicine (ASRM) [2, 3], as well as three or more first
trimester miscarriages, according to the Royal College of
Obstetricians and Gynecologists, UK (RCOG) [4]. Up to
now, various studies have reported that maternal as well
as fetal factors may lead to RPL. Fetal chromosomal ab-
normalities are acknowledged as a significant contributor
to pregnancy loss in approximately 50% of cases. This
pattern is mirrored in our previous study concerning chro-
mosomal abnormalities in early pregnancy losses (EPLs).
In that study, chromosomal abnormalities were detected
in 56.25% of uncontaminated products of conceptions
(POCs), aligning with this observed trend [5]. Additionally,
maternal endocrine dysregulations, autoimmune disorders,
anatomical abnormalities, maternal thrombophilia, as well
as genetic factors can contribute to RPL [6]. Concerning
genetic factors, in a recent study that was designed and
executed in our laboratory, we detected a high incidence of Joubert Syndrome among a group of EPLs (2.03%),
indicating that fetal monogenic diseases can be a common
cause of EPLs [7]. Still, in a large portion of RPL cases,
the exact cause is not clearly identified, and these cases
are referred as idiopathic RPL [8].
Angiogenesis is a physiological process through
which new blood vessels are formed. Decreased angio-
genesis has been associated with several adverse preg-
nancy outcomes, such as infertility, preeclampsia, miscar-
riage, intrauterine fetal distress/growth restriction, and
in severe cases, fetal demise. The Annexin A5 protein,
encoded by the ANXA5 gene, is found in abundance to
hinder coagulation within the placenta and during the early
angiogenesis. When calcium is present, Annexin A5 can
attach to phosphatidylserine situated on the upper surface
of syncytiotrophoblasts in the placenta to prevent clotting
of maternal blood in the intervillous space. Additionally,
the ANXA5 gene plays a crucial role in promoting epithe-
lial repair, upholding placental integrity [9]. Studies have
indicated that the activity of ANXA5 in placental tissue
samples collected from patients with RPL was significantly
diminished, accompanied by a suppressed ANXA5 expres-
sion. These findings imply that a decrease in Annexin A5
protein expression elevates the risk of RPL, especially
in early pregnancy [10]. Bogdanova et al. first reported
that the combination of certain single nucleotide chang-
es: rs28717001 (c.-210A>C), rs28651243 (c.-184T>C),
rs112782763 (c.-229G>A) and rs113588187 (c.-135G>A)
in the promoter region of ANXA5 was associated with an
increased risk of recurrent miscarriages. All four changes
were defined as M2 haplotype, and the first two were des-
ignated as M1 haplotype [11]. As mentioned in a recent
meta-analysis study [12], and a review article [13], dealing
with the effect of the ANXA5 haplotypes on RPL, several
case-control studies have shown a favorable correlation
between the M2/ANXA5 haplotype and RPL across di-
verse ethnic populations, including cohorts from Germany
[11, 14, 15], Japan [16], the United Kingdom [17] Italy
[18] China [19] Malaysia [20] and Greece [21]. However,
contrasting results were observed in studies involving the
Chinese and Danish/Estonian ethnic groups. These groups
did not reveal any association between the M2/ANXA5
haplotype and RPL [22, 23].
The human placenta is rich in angiogenic factors such
as VEGF, standing out as the most potent stimulator of
angiogenesis. VEGF plays a crucial role in endometrial
readiness, implantation, and the development of placen-
tal and fetal blood vessels in early pregnancy, and in the
vascular adaptation during pregnancy in the mother [24].
Several single nucleotide changes (SNPs) have been identi-
fied in the VEGFA gene, affecting VEGF-A activity and
expression. The most significant finding in most studies is that presence of the c.-1154G/A (rs1570360) variant is
associated with recurrent early pregnancy losses in contrast
to normal control groups. The earliest study demonstrating
a significant difference goes back to 2005 in Greece [25].
The study involved 52 women with 3 or more recurrent
pregnancy losses and 82 controls with live births and no
history of pregnancy loss. The analysis of allele frequen-
cy for the polymorphic variant c.-1154G/A (rs1570360)
yielded a p-value of 0.016, indicating an increased allelic
frequency of the mutant allele A in patients with early
pregnancy losses. The c.*237C>T variant (rs3025039)
increases VEGFA expression as well and acts in a simi-
lar direction [26, 27]. Similarly, the effect of the variants
in the ANXA5 gene have been shown in some studies to
contribute negatively to the rs1570360 and rs3025039
variants in susceptibility to recurrent miscarriages in dif-
ferent geographic groups [27, 28, 29]. Yet others have not
confirmed this association [30, 31], therefore the need for
further research to see if these relations exist. Hence, these
allelic variants are unquestionably noteworthy in investi-
gating the predisposition to RPL development.
In establishing an effective and cost-efficient method
for variant detection based on multiplex single-base ex-
tension, we aimed to examine the association of the c.-
210A>C, c.-184T>C, c.-229G>A, c.-135G>A variants in
the ANXA5 gene and c.-1154G>A, c.*237C>T variants in
the VEGFA gene in a cohort of women with early pregnan-
cy losses, compared to a control group of women without
pregnancy loss and at least one live birth. Moreover, the
determination of the status of these variants would provide
a direction for future therapies in women with unexplained
pregnancy losses, since the large amount of data suggest
that the M2/ANXA5 haplotype may contribute to the oc-
currence of this condition.
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