title: 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.
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK. mariaencisolorences@gmail.com.
authors.forename: María
authors.initials: M
authors.lastname: Enciso
authors.affiliation: Reprogenetics UK Ltd., Institute of Reproductive Sciences, Oxford, UK.
authors.forename: Jonás
authors.initials: J
authors.lastname: Sarasa
authors.affiliation: Preimplantation Genetics Group, Institute for Women's Health, University College London, London, UK.
authors.forename: Leoni
authors.initials: L
authors.lastname: Xanthopoulou
authors.affiliation: Recombine, New York, NY, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Bristow
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK.
authors.forename: Megan
authors.initials: M
authors.lastname: Bowles
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK.|Reprogenetics UK Ltd., Institute of Reproductive Sciences, Oxford, UK.
authors.forename: Elpida
authors.initials: E
authors.lastname: Fragouli
authors.affiliation: Preimplantation Genetics Group, Institute for Women's Health, University College London, London, UK.
authors.forename: Joy
authors.initials: J
authors.lastname: Delhanty
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK. dagan.wells@obs-gyn.ox.ac.uk.|Reprogenetics UK Ltd., Institute of Reproductive Sciences, Oxford, UK. dagan.wells@obs-gyn.ox.ac.uk.
authors.forename: Dagan
authors.initials: D
authors.lastname: Wells
mesh_terms: D000328:Adult; D000782:Aneuploidy; D015331:Cohort Studies; D004624:Embryo Transfer; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D005307:Fertilization in Vitro; D006801:Humans; D007246:Infertility / Q000453:epidemiology* / Q000235:genetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011247:Pregnancy; D006113:United Kingdom / Q000453:epidemiology
chemical_list: C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)