Balkan Journal of Medical Genetics

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

RESULTS

Couples with Unexplained Fertility Problems. We analyzed 100 couples, a total of 200 individuals (average age 32.9 years, median age 33 years), 100 females (average and median age 32 years, range 21- 44 years) and 100 males (average age 33.75 years, median age 34 years, range 23-44 years). The control group included 222 healthy blood donors (average and median age 43 years), 111 females (average and median age 42 years, range 27-66 years) and 111 males (average and median age 44 years, range 21- 71 years). Genotypes and allele frequencies were compared separately for both MTHFR mutations between all groups of probands and controls. A statistically significant shift in allele frequency of the C677T mutation, an increase of the minor T allele frequency was observed. There were no significant differences in genotype frequencies for both mutations, whereas HWE was observed in both groups and for both mutations. When genotype frequencies were stratified according to gender we did not observe any differences in distribution of the data when female probands were compared to female controls and the HWE was maintained in all groups. However, in the group of male probands there was an increase of C677T mutation TT homozygotes and a corresponding decrease of CC homozygotes (Table 1). Consequently the T allele frequency was also significantly increased in male probands (p <0.05, Table 1). The analysis of the A1298C mutation did not show any significant differences between male probands and male controls despite the fact that HWE was not maintained in the group of male probands (Table 1). When combined genotype frequencies were compared between probands and controls, only males contributed to the significant difference in genotype distribution (p <0.001; see Table 2). Additionally, the haplotype distributions between the probands and controls were compared. The analysis was performed under the assumption that compound heterozygotes had minor alleles exclusively in the trans position. We did not observe any significant differences in haplotype frequencies between both groups of individuals. Spontaneously Aborted Embryonic Tissue Samples. We also analyzed 353 samples of embryonic tissues from spontaneous abortions. All were karyotyped, and in samples without a viable cell culture, the genomic DNA was analyzed with the MLPA method to detect any aneuploidies. Major chromosomal aberrations, mostly trisomies and polyploidies, were detected in 131 samples (37.1%) whereas a normal karyotype was present in the remaining 222 samples (62.9%). The genotype distribution of the MTHFR C677T mutation differed significantly in the SAET group compared to the control group (see Table 3). Hardy- Weinberg equilibrium was not present in the proband group. This deviation was caused by a substantial increase of the number of TT genotypes, which also significantly increased the 677T allele frequency (Table 3). Consequently, the CC genotype was under represented. Interestingly, HWE was also not present in the SAET samples for the A1298C mutation; however, genotype distribution did not differ significantly and neither did the allele frequencies (Table 3). When the SAET samples were divided according to the presence of the aneuploidy, both subgroups showed comparable and significant increases in 677T allele frequency and genotype TT frequency. The allele and genotype frequencies of the A1298C mutation did not differ significantly between both subgroups of SAET samples. Hardy-Weinberg equilibrium was not present in the subgroup of SAET samples with normal karyotype for both MTHFR mutations. The distribution of combined genotypes in SAET samples differed significantly from controls and the majority of the change was attributed to the increased presence of TTAC and TTCC genotypes (Table 4). Both subgroups of SAET samples showed little difference in their genotype distribution (p = 0.21; Table 4). Finally, the haplotype frequencies were analyzed in compound heterozygotes. Three out of four possible haplotypes differed significantly between SAET samples and controls; haplotypes with 677C were under represented, whereas TC, the two minor allele haplotypes were significantly over represented in SAET samples (see Table 5).

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