MTHFR C677T AND A1298C GENOTYPES AND HAPLOTYPES
IN SLOVENIAN COUPLES WITH UNEXPLAINED
INFERTILITY PROBLEMS AND IN EMBRYONIC TISSUES
FROM SPONTANEOUS ABORTIONS
Stangler Herodež Š1,*, Zagradišnik B1, Erjavec Škerget A1,
Zagorac A1, Takač I2,3, Vlaisavljević V4, Lokar L5, Kokalj Vokač N1,2
*Corresponding Author: Dr. Špela Stangler Herodež, Laboratory of Medical Genetics, University Clinical Centre
Maribor, Ljubljanska ulica 5, 2000 Maribor, Slovenia; Tel.: 386-2-321-27-37; Fax.: 386-2-321-27-55; E-mail:
spela.sh@ukc-mb.si
page: 31
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DISCUSSION
The MTHFR C677T and A1289C polymorphisms
are important thrombophilic factors that might
be associated with infertility and recurrent spontaneous
abortion (RSA) [25]. In the present study, we
evaluated the MTHFR C677T and A1298C genotype
and haplotype distributions in couples with UFP and
healthy controls, and determined the MTHFR C677T
and A1298C genotype and haplotype associations
with compromised fetal viability with regard to the
presence of aneuploidies.
The present study has certain limitations. In the
case of the group with UFP, HWE was not present
in all the tested groups (see results). However, in the
control group, HWE was present, which means that the difference in the tested groups is probably due to
biological differences rather than recruitment bias.
Such results have previously been reported in the
studies with certain patient subgroups that were also
without HWE for MTHFR polymorphisms [26,27].
The same observation was made in the group of SAET
with absent HWE for both MTHFR polymorphisms
before and after stratification for aneuploidy. In this
case, similar results have not previously been reported.
Larger samples may be needed in order to resolve
these limitations. Despite limitations, our study was focused
on the relationship between the MTHFR C677T/
A1298C genotypes/haplotypes and fertility problems
of grown adults and SAETs in a Slovenian population.
We found significant difference in the prevalence
of MTHFR C677T/A1298C polymorphisms in probands
with UFP compared to controls without an infertility
history. Only male probands contributed to the
association, indicating that MTHFR mutation may be
a gender-specific factor that affects fertility of grown
adults. This single male contribution was expected,
while it has been reported for male adults affected with
infertility [6-8]. On the other hand, it may be consistent
with the role of the MTHFR gene in spermatogenesis
also mentioned in previously reported studies [5,7].
Altered DNA methylation patterns of the MTHFR
promoter in sperm cells from infertile males indicate
a possible mechanism that may help explain the observed
association [28,29]. Also, we excluded from
the study couples who were affected with known male
infertility factors which possibly increased the likelihood
of identifying the association with the MTHFR
gene. Whether the MTHFR polymorphism C677T
was directly involved in epigenetic phenomena or just
identified an important genetic locus through linkage
disequilibrium remains to be determined. Therefore, the observed asymmetry between both genders may be
a consequence of the differential role that the MTHFR
gene may have in the gametogenesis. Consequently,
no association was observed for female UFP probands
despite the fact that the sample included individuals
who were affected by RSA.
Interestingly, the observed association between
MTHFR polymorphisms and couples with UFP was
entirely the consequence of the increase in the frequency
of the 677T allele, whereas the A1298C polymorphism
contribution was not present. This difference
in contribution of each MTHFR polymorphism
influenced the combined genotype distributions
(Table 2), as well as haplotype distributions, and it
clearly shows the increased importance of the C677T
polymorphism over the A298C polymorphism.
The present study also demonstrated that SAET
exhibit both a significantly higher frequency of the
MTHFR 677TT genotype and a lower frequency of the
677CC genotype, and a moderately higher frequency
of the 1298CC genotype, compared to the controls. In
addition, the MTHFR 677CT, 1298AA and 1298AC
genotypes were similar between the SAETs and the
controls. These results are of interest because they are
different from the results from other studies. Moreover,
Jeehyeon et al. [4] detected a higher proportion
of aborted embryos with the 677CC genotype and a
lower frequency of the 677CT genotype compared to
their control group. On the other hand, Zetterberg et al.
[15] detected a higher proportion of aborted embryos
with the 677CT and 1298AC genotypes compared to
their control group. This inconsistency among studies
may partly be due to a different MTHFR genotype distribution
between groups with different ethnic origins,
or it may be affected by different criteria for SAET
sample collection and from the selection criteria for
the control sample.
Furthermore, we observed all nine possible
combined genotypes of MTHFR C677T/A1298C
from both the SAET and controls. This observation
is contrary to the conclusions of Jeehyeon et al. [4]
who stated that some combinations of C677T and
A1298C alleles may have a severe effect on the fetus.
Thus, the embryo is unable to survive, suggesting the
pivotal role of the MTHFR gene in human development.
However, we agree with Jeehyeon et al. [4]
that more thorough analysis of the MTHFR polymorphism,
based on embryos at a very early stage, should
be conducted before a final conclusion is drawn.
The combined karyotype/MLPA analysis showed
that approximately 37.0% of the SAET samples had
a chromosomal abnormality, but the frequency of
the MTHFR C677T and A1298C genotypes were
not related to chromosomal status in the SAET samples.
The observed association is again caused by
the over representation of the 677T allele, which in
turn, significantly changed the combined genotype
distribution as well as the haplotype distribution.
The minor allele combination (CT) was the main
contributor to the association. The data also identified
the C677T polymorphism as significantly more
important in comparison to the A1298C with regard
to the MTHFR influenced fetal viability.
In conclusion, our data highlight an interesting
possibility that MTHFR polymorphisms may be implicated
as male fertility factors in Slovenian couples
with UFP. No such association was observed in female
probands. With the analysis of SAET samples
we confirmed the association of the MTHFR polymorphisms,
especially the C677T, with the recurrent
early spontaneous abortions.
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