Abstract：
BACKGROUND: Several studies around the world support the hypothesis that genetic polymorphisms involved in folate metabolism could be related to the maternal risk for Down syndrome (DS). Most of them investigated the role of MTHFR C677T and/or A1298C polymorphisms as maternal risk factors for DS, but their results are often conflicting and still inconclusive.
METHODS: We conducted a systematic review and meta-analysis to clarify the association of MTHFR C677T and/or A1298C polymorphisms with the maternal risk of DS. Our search strategy selected 42 eligible case control studies for a total of 4131 case mothers and 5452 control mothers. The Newcastle-Ottawa Scale was used to assess the methodological quality of the selected studies. To assess the confidence of statistically significant associations we applied false positive report probability test, and we performed the trial sequential analysis to minimize the type I error and random error.
RESULTS: We observed significant associations between the MTHFR C677T polymorphism and maternal risk for DS for each of the genetic models investigated (dominant, recessive, codominant, and allelic contrast). Subgroup analysis by region revelated significant association in the Asian population for all the genetic models investigated. Significant associations were also found for certain genetic models in North American, South American, and Middle Eastern populations, while no association was observed in Europeans. The MTHFR A1298C polymorphism did not show any association with the maternal risk of DS, either alone or in combination with the C677T one. The results of false positive report probability to verify the confidence of a significant association suggest that the association between the MTHFR C677T polymorphism and the maternal risk for DS is noteworthy, with high confidence in Asians.
CONCLUSIONS: The results of this meta-analysis support that the MTHFR C677T polymorphism, but not the A1298C one, is associated with the maternal risk for DS. Further studies are required to better characterize the contribution of gene-gene and gene-nutrient interactions as well as those of other regional or ethnic factors that could explain the observed different effect size in different populations.
METHODS: We conducted a systematic review and meta-analysis to clarify the association of MTHFR C677T and/or A1298C polymorphisms with the maternal risk of DS. Our search strategy selected 42 eligible case control studies for a total of 4131 case mothers and 5452 control mothers. The Newcastle-Ottawa Scale was used to assess the methodological quality of the selected studies. To assess the confidence of statistically significant associations we applied false positive report probability test, and we performed the trial sequential analysis to minimize the type I error and random error.
RESULTS: We observed significant associations between the MTHFR C677T polymorphism and maternal risk for DS for each of the genetic models investigated (dominant, recessive, codominant, and allelic contrast). Subgroup analysis by region revelated significant association in the Asian population for all the genetic models investigated. Significant associations were also found for certain genetic models in North American, South American, and Middle Eastern populations, while no association was observed in Europeans. The MTHFR A1298C polymorphism did not show any association with the maternal risk of DS, either alone or in combination with the C677T one. The results of false positive report probability to verify the confidence of a significant association suggest that the association between the MTHFR C677T polymorphism and the maternal risk for DS is noteworthy, with high confidence in Asians.
CONCLUSIONS: The results of this meta-analysis support that the MTHFR C677T polymorphism, but not the A1298C one, is associated with the maternal risk for DS. Further studies are required to better characterize the contribution of gene-gene and gene-nutrient interactions as well as those of other regional or ethnic factors that could explain the observed different effect size in different populations.
摘要：
背景：世界各地的一些研究支持以下假设：叶酸代谢中涉及的遗传多态性可能与唐氏综合征（DS）的母体风险有关。他们中的大多数研究了MTHFRC677T和/或A1298C多态性作为DS的母体危险因素的作用。但是他们的结果往往是相互矛盾的，仍然没有定论。
方法：我们进行了系统评价和荟萃分析，以阐明MTHFRC677T和/或A1298C多态性与母亲DS风险的关联。我们的搜索策略选择了42项符合条件的病例对照研究，共4131例母亲和5452例对照母亲。纽卡斯尔-渥太华量表用于评估所选研究的方法学质量。为了评估具有统计学意义的关联的置信度，我们应用了假阳性报告概率检验，我们进行了试验序贯分析以最小化I型误差和随机误差.
结果：对于所研究的每个遗传模型，我们观察到MTHFRC677T多态性与母亲DS风险之间存在显着关联（显性，隐性,共显性，和等位基因对比)。按地区进行的亚组分析显示，在所有研究的遗传模型中，亚洲人群中存在显着关联。在北美的某些遗传模型中也发现了显着的关联，南美,中东人口，而在欧洲人中没有观察到关联。MTHFRA1298C多态性与DS的母体风险没有任何关联，单独或与C677T结合使用。假阳性报告概率的结果来验证显著关联的置信度，这表明MTHFRC677T多态性与母亲DS风险之间的关联是值得注意的。对亚洲人充满信心。
结论：本荟萃分析的结果支持MTHFRC677T多态性，但不是A1298C,与孕妇患DS的风险有关。需要进一步的研究来更好地表征基因-基因和基因-营养相互作用以及其他区域或种族因素的贡献，这些因素可以解释在不同人群中观察到的不同效应大小。
方法：我们进行了系统评价和荟萃分析，以阐明MTHFRC677T和/或A1298C多态性与母亲DS风险的关联。我们的搜索策略选择了42项符合条件的病例对照研究，共4131例母亲和5452例对照母亲。纽卡斯尔-渥太华量表用于评估所选研究的方法学质量。为了评估具有统计学意义的关联的置信度，我们应用了假阳性报告概率检验，我们进行了试验序贯分析以最小化I型误差和随机误差.
结果：对于所研究的每个遗传模型，我们观察到MTHFRC677T多态性与母亲DS风险之间存在显着关联（显性，隐性,共显性，和等位基因对比)。按地区进行的亚组分析显示，在所有研究的遗传模型中，亚洲人群中存在显着关联。在北美的某些遗传模型中也发现了显着的关联，南美,中东人口，而在欧洲人中没有观察到关联。MTHFRA1298C多态性与DS的母体风险没有任何关联，单独或与C677T结合使用。假阳性报告概率的结果来验证显著关联的置信度，这表明MTHFRC677T多态性与母亲DS风险之间的关联是值得注意的。对亚洲人充满信心。
结论：本荟萃分析的结果支持MTHFRC677T多态性，但不是A1298C,与孕妇患DS的风险有关。需要进一步的研究来更好地表征基因-基因和基因-营养相互作用以及其他区域或种族因素的贡献，这些因素可以解释在不同人群中观察到的不同效应大小。
