Polymorphisms in the MTHFR gene influence embryo viability and the incidence of aneuploidy
Polymorphisms in the MTHFR gene influence embryo viability and the incidence of aneuploidy
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DOI：
10.1007/s00439-016-1652-z
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发表时间：
2016-05-01
期刊：
影响因子：
5.3
通讯作者：
Wells, Dagan
中科院分区：
文献类型：
--
作者：
Enciso, Maria;Sarasa, Jonas;Wells, Dagan
MTHFR是叶酸代谢中的一种重要酶，对生殖功能至关重要。MTHFR序列的变化与生育能力低下有关，但缺乏明确的数据。在本研究中，详细分析了两种常见的MTHFR多态性（C . 677c >T和C . 1298a >C）。此外，首次评估了着床前胚胎中不同MTHFR等位基因的频率。有了几项惊人的发现。首先，结果表明，母亲MTHFR C . 1298a >C基因型强烈影响怀孕发生的可能性，在接受过多次不成功的辅助生殖治疗的妇女中，1298C等位基因的比例明显过高。其次，亲本MTHFR基因型被证明会影响非整倍体胚胎的产生，这表明MTHFR是已知的少数能够调节染色体异常率的人类基因之一。第三，在低生育能力患者中，特别是那些经历过反复胚胎植入失败或流产的患者中，c.677C>T多态性与Hardy-Weinberg平衡存在不寻常的偏离，这可能是罕见的杂合子劣势。最后，描述了MTHFR 677T等位基因对染色体正常胚胎植入能力的巨大影响。这些发现不仅提出了一系列有趣的生物学问题，而且他们还认为，检测MTHFR可能具有很大的临床价值，可以识别植入失败高风险的患者，并在体外受精（IVF）周期中揭示最有活力的胚胎。
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.