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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RESULTS
ANXA5 variants
Haplotype-based classification
Given that the four alterations collectively constitute
a haplotype, it is possible to categorize them based on the haplotype’s representation, the extent to which the M1
haplotype (comprising two changes) and the M2 haplotype
(encompassing all four changes) are present. Moreover,
various subcategories can be delineated to observe dif-
ferent combinations (haplotypes), including N/N (normal
genotype), N/M1 (heterozygous for haplotype M1), M1/
M1 (homozygous for haplotype M1), N/M2 (heterozygous
for haplotype M2), M2/M2 (homozygous for haplotype
M2), and M1/M2 (double heterozygous). All our examined
samples belonged to one of the above-mentioned catego-
ries, i.e., a non-haplotype affiliation was not present in
either of our cohorts.
We observed that the suggested pathological haplo-
types (M1, M2 and their combinations) were more abun-
dant among our group of women with EPLs, evident by the
fact that the normal genotype was found to be significantly
more frequent in the control group, with a p-value=0.0009.
The M2 heterozygous haplotype was significantly more
prevalent among the women with EPLs group, reaching a
p-value of 0.0006. The heterozygous M1 and homozygous
M2 haplotypes were both more frequent among the group
of women with EPLs, however these differences did not
reach statistical significance. Interestingly, no homozygous
M1 and M1/M2 compound heterozygous haplotypes were
detected among the patients group, while the control group
included 1 and 5 representatives for each haplotype com-
bination. These findings are presented in Table 3.
Comparison based on history of pregnancy loss
and live births
Similarly, in these categorizations, our findings indi-
cated a significantly higher frequency of the normal geno-
type observed in the control group, highlighting that the
pathological M1, M2 haplotypes and their combinations
were more prevalent among the women who had experi-
enced EPL in our study (p-value=0.0001). Remarkably,
statistically significant outcomes were noted for the pres-
ence of heterozygotes for the M2 haplotype in individu-
als who had experienced one early pregnancy loss, when
compared to the controls, a pattern also observed in those with recurrent EPLs, however with borderline p-value of
0.057. Further, the occurrence of heterozygous M1 and ho-
mozygous M2 haplotypes were equally distributed in both
categorizations and did not achieve statistical significance
in comparison to the corresponding haplotypes observed
in the controls (data presented in Supplementary Table 1).
Notably, among the women with EPLs and without
a live birth, there was a statistically significant higher
prevalence of heterozygotes for haplotype M2 compared
to the control group. Also, the homozygotes for the M2
haplotype belonged to this subgroup of women with EPLs
and without a live birth. The women with EPLs and a live
birth showed higher presence of heterozygotes for the
M1 haplotype, with a borderline statistical significance
(p-value=0.05), as presented in Supplementary Table 1.
Comparison based on maternal age
and on gestational week of the current pregnancy
among the women with EPLs
When the maternal age (at the time of admission) was
taken in consideration in our cohort, we observed statisti-
cally significant higher prevalence of the heterozygous M2
haplotype among the women with EPLs, ≤ 30 years of age
(p-value=0.003) and ≥ 36 years of age (p-value=0.01), in
comparison to the control group of the same age range. In
contrast, the group of examined women between 31 and 35
years of age, presented a statistically significant difference
in the heterozygous M1 haplotype amid the two cohorts
(p-value=0.03), with this haplotype being more frequent
among the women with EPLs. These data are presented
in Supplementary Table 2.
A comparison based on gestational week of the cur-
rent pregnancy was also performed and these findings
are presented in Supplementary Table 2 as well. Unfortu-
nately, data on this parameter was missing for more than
a third (35.3%) of the women with EPLs. We divided the
women in two major groups, the first having pregnancy
loss between weeks 6-9, and the second group consisted
of women with EPLs in weeks 10 and 11, based on the
presumption that women carrying the M2 haplotype are believed to face over twice the risk of fetal loss between
10 and 15 weeks of gestation compared to those who do
not carry this haplotype. Again, the heterozygous M2 hap-
lotype was significantly more present in both subgroups of
women with EPLs, compared to the controls, reaching a
p-value of 0.008 and 0.007 for both subgroups respectively.
VEGFA gene
The genotypic frequency of the two examined vari-
ants in the two specified groups are displayed in Table 4.
The results indicate the absence of a statistically signifi-
cant difference of the selected VEGFA variants between
women with EPLs and the control group. The VEGFA c.-
1154G/A (rs1570360) variant was identified in 76 patients
(40%), in heterozygous state and in 22 (11.58%) patients
in homozygous state. In the control group, 70 individuals
were heterozygous (36.84%), while 21 (11.05%) were
homozygous for this variant. The c.*237C/T (rs3025039)
presented similar distributions between the women with
EPLs and the controls, however, the homozygous mutant
genotype was more rarely found in both groups, when com-
pared to the c.-1154G/A (rs1570360) variant. Further, two
women with EPL were found to be homozygous for both
VEGFA variants (2/190, 1.05%), and 20 women with EPLs
were heterozygous for the both VEGFA variants (20/190,
10.53%). Among the control group, those numbers were
one (1/190, 0.53%), and 14 (14/190, 7.37%), respectively.
Both differences were not statistically significant (p-val-
ue=0.8, and p-value=0.2, accordingly).
Comparison based on history of pregnancy loss
and previous live birth
The results of the comparison based on history of
pregnancy loss and previous live birth between the two
groups are presented in Supplementary Table 3. Examining
c.-1154G/A (rs1570360), among women with 2 or more
early pregnancy losses, the mutant homozygous form A/A
is represented by 14.68%, compared to 11.05% in the control group. However, this discrepancy did not reach
statistical significance.
Likewise, in the case of the polymorphic variant
c.*237C/T (rs3025039), no notable difference was ob-
served in the subgroups of women with EPLs, compared
to the controls. The distribution of the mutant form T/T
was higher in the group of women with 2 or more EPLs,
although the difference compared to the control group was
not statistically significant.
Regarding previous live births, the patients were
categorized into two groups: one comprised patients
with early pregnancy loss and no prior live births, and
the other included those with early pregnancy loss and at
least one live birth. The group of women with EPLs and
a live birth consisted of 39 cases, among which, 53.85%
expressed heterozygosity for the c.-1154G/A (rs1570360)
variant, compared to the 36.84% among the controls, and
this difference was found to be statistically significant
(p-value=0.04). Amid the subgroup of women with EPLs
and a live birth, the genotypes containing the mutant allele
of the c.-1154G/A (rs1570360) variant, were found to be
more common, compared to the control group where the
normal genotype was most frequent, reaching a borderline
p-value of 0.05. The data on c.*237C/T (rs3025039), for
this parameter did not show statistical significance. These
data are depicted in Supplementary Table 3.
Comparison based on maternal age
and gestational week of the current
pregnancy among the women with EPLs
When maternal age was taken into account, in order
to observe the distribution of the genotypes for the c.-
1154G/A (rs1570360) and c.*237C/T (rs3025039) VEGFA
variants, between the different age groups of the women
with EPLs and controls, no statistically significant differ-
ences were obtained in any subcategory. These data are
presented in Supplementary Table 4.
An analysis was conducted considering the gesta-
tional week of the current pregnancy, and the genotypes of the VEGFA c.-1154G/A (rs1570360) and c.*237C/T
(rs3025039) are displayed in Supplementary Table 4 as
well. As previously noted, information regarding this
parameter was unavailable for over a third (35.3%) of
the women who experienced EPLs. The heterozygous c.-
1154G/A (rs1570360) was much more common among
the subgroup of women with EPLs in week 10-11, reach-
ing p-value 0.03. In the same subgroup, the heterozygous
c.*237C/T (rs3025039) was also more frequent, compared
to the controls, with a borderline p-value of 0.05.
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