Birthweight marks an important milestone of health across the lifespan, including cardiometabolic disease risk in later life. The placenta, a transient organ at the maternal-fetal interface, regulates fetal growth. Identifying genetic loci where DNA methylation in placenta is associated with birthweight can unravel genomic pathways that are dysregulated in aberrant fetal growth and cardiometabolic diseases in later life. We performed placental epigenome-wide association study (EWAS) of birthweight in an ethnic diverse cohort of pregnant women (n = 301). Methylation at 15 cytosine-(phosphate)-guanine sites (CpGs) was associated with birthweight (false discovery rate (FDR) < 0.05). Methylation at four (26.7%) CpG sites was associated with placental transcript levels of 15 genes (FDR < 0.05), including genes known to be associated with adult lipid traits, inflammation and oxidative stress. Increased methylation at cg06155341 was associated with higher birthweight and lower FOSL1 expression, and lower FOSL1 expression was correlated with higher birthweight. Given the role of the FOSL1 transcription factor in regulating developmental processes at the maternal-fetal interface, epigenetic mechanisms at this locus may regulate fetal development. We demonstrated trans-tissue portability of methylation at four genes (MLLT1, PDE9A, ASAP2, and SLC20A2) implicated in birthweight by a previous study in cord blood. We also found that methylation changes known to be related to maternal underweight, preeclampsia and adult type 2 diabetes were associated with lower birthweight in placenta. We identified novel placental DNA methylation changes associated with birthweight. Placental epigenetic mechanisms may underlie dysregulated fetal development and early origins of adult cardiometabolic diseases. ClinicalTrials.gov, NCT00912132

中文翻译：

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胎盘中的 DNA 甲基化位点与出生体重和早期发育和成人疾病相关基因的表达有关。

出生体重标志着整个生命周期健康的一个重要里程碑，包括晚年的心脏代谢疾病风险。胎盘是母胎界面的一个短暂器官，调节胎儿的生长。确定胎盘中 DNA 甲基化与出生体重相关的基因位点可以解开在胎儿生长异常和晚年心脏代谢疾病中失调的基因组通路。我们在不同种族的孕妇队列（n = 301）中进行了出生体重的胎盘全表观基因组关联研究（EWAS）。15 个胞嘧啶-（磷酸）-鸟嘌呤位点 (CpG) 的甲基化与出生体重相关（错误发现率 (FDR) < 0.05）。四个 (26.7%) CpG 位点的甲基化与 15 个基因的胎盘转录水平相关（FDR < 0.05），包括已知与成人脂质特征、炎症和氧化应激相关的基因。cg06155341 甲基化增加与较高的出生体重和较低的 FOSL1 表达相关，较低的 FOSL1 表达与较高的出生体重相关。鉴于 FOSL1 转录因子在调节母胎界面发育过程中的作用，该位点的表观遗传机制可能会调节胎儿发育。我们通过先前的脐带血研究证明了与出生体重有关的四个基因（MLLT1、PDE9A、ASAP2 和 SLC20A2）甲基化的跨组织可移植性。我们还发现，已知与母亲体重不足、先兆子痫和成人 2 型糖尿病相关的甲基化变化与胎盘出生体重降低有关。我们确定了与出生体重相关的新胎盘 DNA 甲基化变化。胎盘表观遗传机制可能是胎儿发育失调和成人心脏代谢疾病早期起源的基础。ClinicalTrials.gov, NCT00912132