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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DISCUSSION
In this study, we have developed a SNaPshot geno-
typing technique, which identifies four distinct variants
in the ANXA5 gene and two variants in the VEGFA gene.
The method efficiently and concurrently identifies all six
selected variants and also stands out for its simplicity,
accuracy, ease of execution, and cost-effectiveness. By
employing this method, we have assessed the occurrence
rates of the two haplotypes (M1 and M2) within the ANXA5
gene and the two variants (c.-1154G/A (rs1570360) and
c.*237C/T (rs3025039)) within the VEGFA gene among
selected group of women of Macedonian and Albanian
ethnic origin experiencing early pregnancy loss. Our analy-
sis involved comparing these rates to controls matched by
ethnicity and age.
Given the inconsistencies in the literature regarding
the impact of the specified variants, as outlined in the
introduction, the primary objective of our study was to
investigate whether the six selected variants are linked to
an elevated risk of early pregnancy loss, particularly within
our two major ethnical groups (Macedonian and Albanian).
It is important to emphasize that in our examined popula-
tion fetal aneuploidy as a reason for EPLs was excluded.
Considering that the majority of studies have focused
on individuals with subsequent pregnancy losses, and giv-
en the predominant nulliparous status among most patients,
it became crucial to examine the distribution of haplotypes
within various subgroups of our patients. Bogdanova et
al. revealed four consecutive single nucleotide changes
in the ANXA5 promoter, which are transmitted as a hap-
lotype called M2 that reduces promoter activity, thereby
leading to reduced production of Annexin A5 mRNA as
well as M1 haplotype covering the first two nucleotide
substitutions. Certain analyzes showed that haplotypes
M1 and M2 reduce ANXA5 promoter activity by 40% and
60%, respectively, thereby significantly affecting ANXA5
expression. Women with the M2 haplotype are thought to
have more than a 2-fold higher risk of fetal loss between
10 and 15 weeks of gestation than non-carriers [11]. As
highlighted in a recent meta-analysis [12] and a review [13] examining the impact of the ANXA5 haplotypes on recur-
rent pregnancy loss (RPL), multiple case-control studies
have demonstrated a positive association between the M2/
ANXA5 haplotype and RPL across a range of ethnic back-
grounds [11, 14-21].
In line with numerous studies, supporting the concept
that M2 and M1 ANXA5 haplotypes are more common in
patients experiencing pregnancy loss [10-21], our study
presented higher frequency of the M2 haplotype among the
women with EPLs compared to controls (p-value=0.0006).
Furthermore, when we did several sub categoriza-
tions, we observed evident statistical significance of the
M2 haplotype among: women with recurrent as well as
sporadic early pregnancy loss (p-value=0.057 and p-val-
ue<0.00001 respectively), women with EPLs and no live
birth (p-value=0.0003), women ≤30 and ≥36 years of age
(p-value=0.003 and p-value<0.001 respectively), and also
in both subgroups of pregnancy loss between 6-9 GW
and 10-11GW (p-value=0.008 and p-value<0.007 accord-
ingly). The M1 haplotype was found to be more prevalent
in the subgroup of women with EPLs and a live birth
(p-value=0.05) and in the subgroup of women with ages
between 31 and 35 years with a p-value of 0.01.
Furthermore, there are studies indicating that low-
molecular-weight heparin might have a positive effect
on miscarriage rate and recurrent implantation failure in
treated M2/ANXA5 haplotype carriers [36, 37], so, a re-
search in this direction could be a further step.
VEGFA has gathered significant attention due to its
pivotal role in angiogenesis, particularly notable for its im-
plications in embryo development. Compelling evidence
underscores its critical involvement in fetal and placental
angiogenesis, suggesting that vascular formation irregu-
larities or dysfunction contribute to RPL. Additionally,
first-trimester trophoblast VEGFA expression was found to
be weaker in placental samples from RPL cases compared
to gestational age-matched normal placenta [38, 39]. 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 [25-29], while others have not confirmed
the association [30, 31], so the need for further research
of these relations exists. According to a meta study by Xu
et al., [27] the c.-1154G/A (rs1570360) and c.*237C/T
(rs3025039) variant demonstrated statistical significance
concerning RPL risk across different geographical popula-
tions, and discrepancies such as in our present study may
be explained by the small sample size and substantial er-
rors from estimation.
In our examined cohort, we observed a general higher
prevalence of the heterozygous and mutant homozygous
genotypes for the both VEGFA variants, compared to the controls, however without statistical significance. Nev-
ertheless, we noticed borderline statistically significant
difference (p-value=0.05) in heterozygotes for the c.-
1154G/A (rs1570360) variant between the women with
EPLs and a live birth, compared to the controls. Also, when
we analyzed the results from the division based on gesta-
tional week of the last pregnancy, we noticed statistically
higher frequency of the heterozygous genotypes for both
VEGFA variants with a p-value<0.00001 for c.-1154G/A
(rs1570360) and p-value=0.05 for c.*237C/T (rs3025039).
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