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Polymorphisms in the MTHFR gene influence embryo viability and the incidence of aneuploidy

Abstract

MTHFR is an important enzyme in the metabolism of folic acid and is crucial for reproductive function. Variation in the sequence of MTHFR has been implicated in subfertility, but definitive data are lacking. In the present study, a detailed analysis of two common MTHFR polymorphisms (c.677C>T and c.1298A>C) was performed. Additionally, for the first time, the frequencies of different MTHFR alleles were assessed in preimplantation embryos. Several striking discoveries were made. Firstly, results demonstrated that maternal MTHFR c.1298A>C genotype strongly influences the likelihood of a pregnancy occurring, with the 1298C allele being significantly overrepresented amongst women who have undergone several unsuccessful assisted reproductive treatments. Secondly, parental MTHFR genotypes were shown to affect the production of aneuploid embryos, indicating that MTHFR is one of the few known human genes with the capacity to modulate rates of chromosome abnormality. Thirdly, an unusual deviation from Hardy–Weinberg equilibrium was noted for the c.677C>T polymorphism in subfertile patients, especially those who had experienced recurrent failure of embryo implantation or miscarriage, potentially explained by a rare case of heterozygote disadvantage. Finally, a dramatic impact of the MTHFR 677T allele on the capacity of chromosomally normal embryos to implant is described. Not only do these findings raise a series of interesting biological questions, but they also argue that testing of MTHFR could be of great clinical value, identifying patients at high risk of implantation failure and revealing the most viable embryos during in vitro fertilisation (IVF) cycles.

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Acknowledgments

Maria Enciso is funded by the Spanish Ministerio de Educacion Cultura y Deporte Fellowship. Dagan Wells is funded by the Oxford NIHR Biomedical Research Centre.

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Correspondence to María Enciso or Dagan Wells.

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M. Enciso and J. Sarasa contributed equally to this work.

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Supplementary material 1 (DOCX 26 kb)

439_2016_1652_MOESM2_ESM.tif

Supplementary material 2 (TIFF 4758 kb) Fig. S1 Distribution of MTHFR c.677C>T genotype frequencies in subfertile populations and predicted frequencies based upon Hardy-Weinberg. Compliance with the Hardy-Weinberg equilibrium was assessed using GENEPOP v.4.2. All populations shown in this graph present a deviation from Hardy-Weinberg equilibrium due to a deficit of heterozygotes

439_2016_1652_MOESM3_ESM.tif

Supplementary material 3 (TIFF 7144 kb) Fig. S2 Distribution of MTHFR c.677C>T genotype frequencies in an independent set of samples investigated using CarrierMap test (Recombine) and predicted frequencies based upon Hardy-Weinberg. Compliance with the Hardy-Weinberg equilibrium was assessed using GENEPOP v.4.2. All populations shown in this graph present a deviation from Hardy-Weinberg equilibrium due to a deficit of heterozygotes

439_2016_1652_MOESM4_ESM.tif

Supplementary material 4 (TIFF 8042 kb) Fig. S3 Distribution of MTHFR c.677C>T genotype frequencies in euploid preimplantation embryos with failed implantation and the adult population composed of fertile and subfertile individuals. X2 test was used to estimate whether the genotypic frequencies differed significantly among the study groups. Significantly different groups (p<0.05) are highlighted with an asterisk

439_2016_1652_MOESM5_ESM.tif

Supplementary material 5 (TIFF 7465 kb) Fig. S4 Distribution of MTHFR c.677C>T genotype frequencies in euploid preimplantation embryos with successful and failed implantation and predicted frequencies based upon Hardy- Weinberg. Compliance with the Hardy-Weinberg equilibrium was assessed using GENEPOP v.4.2. No deviation from HWE was detected in any of the groups shown in this graph probably due to small size

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Enciso, M., Sarasa, J., Xanthopoulou, L. et al. Polymorphisms in the MTHFR gene influence embryo viability and the incidence of aneuploidy. Hum Genet 135, 555–568 (2016). https://doi.org/10.1007/s00439-016-1652-z

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Keywords

  • Recurrent Miscarriage
  • Preimplantation Embryo
  • MTHFR Gene
  • Implantation Failure
  • 1298C Allele