DNA methylation mediates the effect of maternal smoking on offspring birthweight: a birth cohort study of multi-ethnic US mother-newborn pairs.
DNA methylation mediates the effect of maternal smoking on offspring birthweight: a birth cohort study of multi-ethnic US mother-newborn pairs.
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DOI：
10.1186/s13148-021-01032-6
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发表时间：
2021-03-04
影响因子：
5.7
通讯作者：
Ji H
中科院分区：
文献类型：
--
作者：
Xu R;Hong X;Zhang B;Huang W;Hou W;Wang G;Wang X;Igusa T;Liang L;Ji H
在美国，母亲吸烟每年影响超过50万例妊娠，已知会导致胎儿生长受限，这可通过较低的出生体重以及相关的长期后果来衡量。母亲吸烟还与胎儿DNA甲基化（DNAm）改变有关。然而，很大程度上尚未探索的是这些DNAm改变仅仅是吸烟暴露的标志，还是它们对健康结果也有影响。本研究验证了胎儿DNAm介导母亲吸烟对新生儿出生体重影响的假设。
本研究纳入了来自美国一个以城市为主、低收入、多种族的出生队列中的母婴对。使用Illumina Infinium MethylationEPIC BeadChip测定脐带血中的DNAm。在标准的质量控制和标准化程序之后，使用线性回归模型对母亲吸烟进行了全表观基因组关联研究（EWAS），并对母亲年龄、教育程度、种族、产次、孕前体重指数、饮酒量、孕周、母亲孕前/孕期糖尿病、婴儿性别、脐带血细胞组成以及批次效应进行了控制。为了量化脐带DNAm介导吸烟 - 出生体重关联的程度，使用了针对单一中介的范德韦尔 - 范斯特兰特方法以及针对多个中介的结构方程模型，并对相关协变量进行了调整。
该研究纳入了954对母婴。在母亲中，165人（17.3%）在孕前或孕期曾吸烟。有吸烟暴露的新生儿平均比无暴露的新生儿出生体重低258克（P < 0.001）。以错误发现率（FDR）< 0.05作为显著性截断值，EWAS鉴定出38个与母亲吸烟相关的差异甲基化CpG位点。其中，17个CpG位点定位到先前报道的基因：GFI1、AHRR、CYP1A1和CNTNAP2；位于前三个基因中的8个位点，经邦费罗尼校正后与新生儿出生体重显著相关，并介导了吸烟 - 出生体重关联。这三个基因的综合中介效应解释了67.8%的吸烟 - 出生体重关联。
我们的研究不仅进一步支持了母亲吸烟会改变多种族人群中胎儿DNAm的观点，还表明胎儿DNAm在很大程度上介导了母亲吸烟与出生体重之间的关联。如果我们的发现得到进一步验证，这表明DNAm修饰可能是母亲吸烟损害胎儿生长以及或许甚至长期健康结果的一个重要途径。
Maternal smoking affects more than half a million pregnancies each year in the US and is known to result in fetal growth restriction as measured by lower birthweight and its associated long-term consequences. Maternal smoking also has been linked to altered fetal DNA methylation (DNAm). However, what remains largely unexplored is whether these DNAm alterations are merely markers of smoking exposure or if they also have implications for health outcomes. This study tested the hypothesis that fetal DNAm mediates the effect of maternal smoking on newborn birthweight. This study included mother–newborn pairs from a US predominantly urban, low-income multi-ethnic birth cohort. DNAm in cord blood were determined using the Illumina Infinium MethylationEPIC BeadChip. After standard quality control and normalization procedures, an epigenome-wide association study (EWAS) of maternal smoking was performed using linear regression models, controlling for maternal age, education, race, parity, pre-pregnancy body mass index, alcohol consumption, gestational age, maternal pregestational/gestational diabetes, child sex, cord blood cell compositions and batch effects. To quantify the degree to which cord DNAm mediates the smoking-birthweight association, the VanderWeele-Vansteelandt approach for single mediator and structural equational model for multiple mediators were used, adjusting for pertinent covariates. The study included 954 mother–newborn pairs. Among mothers, 165 (17.3%) ever smoked before or during pregnancy. Newborns with smoking exposure had on average 258 g lower birthweight than newborns without exposure (P < 0.001). Using a false discovery rate (FDR) < 0.05 as the significance cutoff, the EWAS identified 38 differentially methylated CpG sites associated with maternal smoking. Of those, 17 CpG sites were mapped to previously reported genes: GFI1, AHRR, CYP1A1, and CNTNAP2; 8 of those, located in the first three genes, were Bonferroni significantly associated with newborn birthweight and mediated the smoking-birthweight association. The combined mediation effect of the three genes explained 67.8% of the smoking-birthweight association. Our study not only lends further support that maternal smoking alters fetal DNAm in a multiethnic population, but also suggests that fetal DNAm substantially mediates the maternal smoking–birthweight association. Our findings, if further validated, indicate that DNAm modification is likely an important pathway by which maternal smoking impairs fetal growth and, perhaps, even long-term health outcomes.
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影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
影响因子：
9.8
作者：
Joubert, Bonnie R.;Felix, Janine F.;London, Stephanie J.
通讯作者：
London, Stephanie J.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
3.8
作者：
REVELLE, W
通讯作者：
REVELLE, W
影响因子：
5.8
作者：
Aryee, Martin J.;Jaffe, Andrew E.;Irizarry, Rafael A.
通讯作者：
Irizarry, Rafael A.