Association between maternal MTHFR C677T/A1298C combination polymorphisms and IVF/ICSI outcomes: a retrospective cohort study.
Association between maternal MTHFR C677T/A1298C combination polymorphisms and IVF/ICSI outcomes: a retrospective cohort study.
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母亲 MTHFR C677T/A1298C 组合多态性与 IVF/ICSI 结果之间的关联：一项回顾性队列研究
DOI：
10.1093/hropen/hoac055
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发表时间：
2023
影响因子：
8.3
通讯作者：
中科院分区：
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摘要研究问题母体5，10-亚甲基四氢叶酸还原酶（MTHFR）C677 T/A1298 C组合多态性对IVF/ICSI的胚胎学和临床结局的作用是什么？我们的研究首次揭示了卵母细胞的成熟潜力随着母亲MTHFR活性的降低而逐渐降低，这是由C677 T/A1298 C多态性联合确定的，而具有中等MTHFR活性的女性的胚胎质量更差。尽管许多先前的研究已经探索了MTHFR多态性与IVF/ICSI结局之间的关联，但由于样本不足，未调整潜在混杂因素和/或分别研究C677 T和A1298 C，结果仍然相互矛盾。很少有研究系统地研究了MTHFR活性的确切作用，该活性由C677 T/A1298 C多态性联合决定，对IVF/ICSI的胚胎学和临床结局有影响。研究设计、样本量、持续时间这是一项回顾性队列研究，调查了2017年5月至2020年5月在北京大学第三医院接受MTHFR基因分型和IVF/ICSI治疗的1160名女性。参与者/材料，设置，方法在我院进行MTHFR基因分型和首次IVF/ICSI治疗的女性被纳入，接受植入前基因检测周期的女性被排除。根据C677 T、A1298 C和C677 T/A1298 C联合基因型将纳入研究的女性分为不同的队列。采用广义线性回归模型对胚胎学结局进行评价，包括获卵率、中期II期卵母细胞数、卵母细胞成熟率、正常受精率和可移植胚胎率。临床结局包括生化妊娠率、临床妊娠率和活产率，采用对数二项回归模型进行评价。所有结果均针对潜在混杂因素进行调整。主要结果和机会的作用具有677 TT/1298 AA组合基因型（以下简称为TT/AA，与其他组合基因型一样）的女性，其酶活性最低，与野生型相比，卵母细胞成熟率较低基因型（P = 0.007）。此外，卵母细胞的成熟率与MTHFR酶活性的下降呈线性下降（P-趋势= 0.001），这是由C677 T/A1298 C基因型组合确定的。具有中等酶活性的CC/AC、CC/CC&CT/AA和CT/AC组合基因型与较低的可移植胚胎率相关（P分别为0.013、0.030和0.039）。野生型基因型和C677 T/A1298 C联合变异基因型妇女的临床结局差异无显著性。我们的研究人群具有可比的胚胎学结局，但临床结局比在我们医院接受IVF/ICSI治疗的其他女性更差。因此，应谨慎概括与临床结局相关的结果。此外，我们没有检测每个患者在怀孕期间的叶酸浓度。然而，这可能对我们的结果没有太大影响，因为几乎所有的研究参与者都在怀孕期间服用了足够的叶酸。我们提供了MTHFR C677 T和A1298 C多态性对IVF/ICSI结局影响的整体观点，这有助于为具有不同MTHFR基因型的女性提供合理的叶酸补充建议，特别是对于那些卵母细胞成熟率低和/或胚胎质量低的女性。研究基金/竞争兴趣本工作得到了国家自然科学基金（31871447，82101677）、国家重点研究发展计划（2019 YFA 0801400）和北京市自然科学基金（7202226）的资助。提交人声明，他们之间没有利益冲突。试验注册编号N/A。
Abstract STUDY QUESTION What are the roles of maternal 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C combination polymorphisms on the embryological and clinical outcomes of IVF/ICSI? SUMMARY ANSWER Our study reveals for the first time that the oocyte maturation potential gradually decreases with a reduction of maternal MTHFR activity determined by combined C677T/A1298C polymorphisms, while embryo quality was worse in women with intermediate MTHFR activity. WHAT IS KNOWN ALREADY Although many previous studies have explored the association between MTHFR polymorphisms and IVF/ICSI outcomes, the results remain contradictory due to inadequate samples, no adjustment for potential confounders and/or the study of C677T and A1298C separately. Few studies have systematically investigated the exact role of MTHFR activity determined by combined C677T/A1298C polymorphisms on the embryological and clinical outcomes of IVF/ICSI. STUDY DESIGN, SIZE, DURATION This is a retrospective cohort study investigating 1160 women who were referred for MTHFR genotyping and IVF/ICSI treatment at Peking University Third Hospital from May 2017 to May 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS Women who were referred for MTHFR genotyping and their first IVF/ICSI treatment at our hospital were included and those undergoing preimplantation genetic testing cycles were excluded. The included women were divided into different cohorts according to their C677T, A1298C and combined C677T/A1298C genotypes. The embryological outcomes, including oocytes retrieved, metaphase II oocytes, oocyte maturation rate, normal fertilization rate and transplantable embryo rate, were evaluated by generalized linear regression models. The clinical outcomes, including biochemical pregnancy rate, clinical pregnancy rate and live birth rate, were evaluated by log-binomial regression models. All outcomes were adjusted for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE Women with the combined 677TT/1298AA genotype (hereafter abbreviated as TT/AA, as with other combined genotypes), whose enzyme activity was the lowest, had a lower oocyte maturation rate compared with those with the wild-type genotype (P = 0.007). Moreover, the oocyte maturation rate decreased linearly with the decline in MTHFR enzyme activity determined by combined C677T/A1298C genotypes (P-trend = 0.001). The combined CC/AC, CC/CC&CT/AA and CT/AC genotypes with intermediate enzyme activity were associated with a lower transplantable embryo rate (P = 0.013, 0.030 and 0.039, respectively). The differences in clinical outcomes between women with wild-type genotype and combined C677T/A1298C variant genotypes were not significant. LIMITATIONS, REASONS FOR CAUTION Our study population had comparable embryological outcomes but worse clinical outcomes than other women undergoing IVF/ICSI treatment at our hospital. Therefore, the results related to the clinical outcomes should be generalized with caution. In addition, we did not detect the folate concentration of each patient during pregnancy. However, this might not have much influence on our results because almost all of our study participants took sufficient folic acid around pregnancy. WIDER IMPLICATIONS OF THE FINDINGS We provide a holistic view of the effect of MTHFR C677T and A1298C polymorphisms on the IVF/ICSI outcomes, which can contribute to providing reasonable folic acid supplementation suggestions for women with different MTHFR genotypes, especially for those with a low oocyte maturation rate and/or low embryo quality. STUDY FUNDING/COMPETING INTERESTS This work was funded by the National Natural Science Foundation of China (31871447, and 82101677), the National Key Research and Development Program (2019YFA0801400) and the Natural Science Foundation of Beijing Municipality (7202226). The authors declare that they have no competing interests. TRIAL REGISTRATION NUMBER N/A.
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