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

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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