NEJM:科学家找到6个与妊娠早产相关的基因,它们是……
2017/09/08
大概有5%~15%的妊娠女性会出现“早产”现象,这是遗传因素和环境因素的综合作用,其中遗传占有30%~40%的比例。近日,《新英格兰医学杂志》(NEJM)报道发现了6个与妊娠期和/或早产风险有关的基因,将有助于临床医生识别早产风险妇女,并制定相应的预防策略。


在我国,大概有5%~15%的妊娠女性会出现“早产”现象,即在怀孕未满37周分娩婴儿,其中约15%的早产者死于新生儿期。医学上一致认为,早产是遗传因素和环境因素的综合作用。先前的研究表明,遗传占有30%~40%的比例。

9月7日,美国研究人员发表在《新英格兰医学杂志》(NEJM)上的一篇文献指出了6个与妊娠期和/或早产风险有关的基因,这将有助于临床医生识别早产风险妇女,并制定相应的预防策略。

这项研究的主导者、辛辛那提儿童医院医学中心早产研究中心Louis Muglia医学博士说,这项研究采用了全基因组关联研究(GWAS)分析,是首个与“早产”风险相关基因的大型临床研究项目。

从生物分析学的角度而言,数据集越大,特定基因变异与表型之间的联系就越强。曾经最大的GWAS研究调查了约1000例早产女性,而这项研究包含了4个子集共计50000多名女性的队列。

在这个研究中,科学家要求43568名妇女提供他们的怀孕史、唾液样本和来自23andMe的基因检测结果,与来自3个Nordic研究的8643位母亲和4090名婴儿的数据进行了参考比较,结果鉴定了数个SNP位点。研究人员将他们的结果与GWAS目录和GTEx20 数据库比较,发现这些位点存储了基因表达模式的信息。

据研究者介绍,在进行了基因检测的43568名女性中,在37-42周分娩的人群为37803人,占比86.8%,3331人早产(<37周),占比7.6%,2434人士过期产(>42周),占比5.6%。


图1:Results of the Discovery-Stage Genomewide Association Study

文章的第一作者Ge Zhang博士与同事们对15635593个SNPs进行了评估,以寻找与怀孕和早产基因相关的生物学机制。结果发现,有3个基因(EBF1、EEFSEC、AGTR2)与早产有关,3个基因(WNT4、ADCY5和RAP2C)与妊娠期有关这6个基因对妊娠期遗传力的影响为17%,对早产的遗传力影响为23%。


图2:ESR1 Binding at the WNT4 Locus.

GWAS揭示了这6个基因影响妊娠和早产风险的总体影响:

1)ADCY5(5型腺苷酸环化酶)与出生体重有关;

2)癌基因RAP2C与早产有关;

3)Wnt4基因与子宫内膜蜕膜化有关;其SNP改变会与ESR1(雌激素受体1结合),会导致原发性闭经等现象(见图2);

4)EBF1(早期B淋巴细胞因子1)与血压及颈动脉内膜中层厚度连接相关;

5)AGTR2(血管紧张素Ⅱ受体2型)控制胎盘和子宫之间的循环;

6)EEFSEC(硒代半胱氨酸tRNA的特异性真核延伸因子)与具有抗氧化和抗炎作用的蛋白质有关,两者都可以影响出生时间。

参考资料:

Genes Behind Preterm Birth Identified

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  • Genetic Associations with Gestational Duration and Spontaneous Preterm Birth

    BACKGROUND Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. METHODS We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0×10−8) or an association with suggestive significance (P<1.0×10−6) in the discovery set. RESULTS In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother–infant dyads suggested that these variants act at the level of the maternal genome. CONCLUSIONS In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement. (Funded by the March of Dimes and others.)

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