Singapore Institute for Clinical Sciences, A*STAR, 30 Medical Drive, Singapore, 117609, Singapore.
Duke-NUS Medical School, Singapore, Singapore.
Clin Epigenetics. 2019 Feb 11;11(1):26. doi: 10.1186/s13148-018-0599-4.
Preterm birth (PTB), defined as child birth before completion of 37 weeks of gestation, is a major challenge in perinatal health care and can bear long-term medical and financial burden. Over a million children die each year due to PTB complications, and those who survive can face developmental delays. Unfortunately, our understanding of the molecular pathways associated with PTB remains limited. There is a growing body of evidence suggesting the role of DNA methylation (DNAm) in mediating the effects of PTB on future health outcomes. Thus, epigenome-wide association studies (EWAS), where DNAm sites are examined for associations with PTB, can help shed light on the biological mechanisms linking the two.
In an Asian cohort of 1019 infants (68 preterm, 951 full term), we examined and compared the associations between PTB and genome-wide DNAm profiles using both cord tissue (n = 1019) and cord blood (n = 332) samples on Infinium HumanMethylation450 arrays. PTB was significantly associated (P < 5.8e-7) with DNAm at 296 CpGs (209 genes) in the cord blood. Over 95% of these CpGs were replicated in other PTB/gestational age EWAS conducted in (cord) blood. This replication was apparent even across populations of different ethnic origin (Asians, Caucasians, and African Americans). More than a third of these 296 CpGs were replicated in at least 4 independent studies, thereby identifying a robust set of PTB-linked epigenetic signatures in cord blood. Interrogation of cord tissue in addition to cord blood provided novel insights into the epigenetic status of the neonates born preterm. Overall, 994 CpGs (608 genes, P < 3.7e-7) associated with PTB in cord tissue, of which only 10 of these CpGs were identified in the analysis using cord blood. Genes from cord tissue showed enrichment of molecular pathways related to fetal growth and development, while those from cord blood showed enrichment of immune response pathways. A substantial number of PTB-associated CpGs from both the birth tissues were also associated with gestational age.
Our findings provide insights into the epigenetic landscape of neonates born preterm, and that its status is captured more comprehensively by interrogation of more than one neonatal tissue in tandem. Both these neonatal tissues are clinically relevant in their unique ways and require careful consideration in identification of biomarkers related to PTB and gestational age.
This birth cohort is a prospective observational study designed to study the developmental origins of health and disease, and was retrospectively registered on 1 July 2010 under the identifier NCT01174875 .
早产（PTB）定义为妊娠 37 周前分娩，是围产期保健的主要挑战，会带来长期的医疗和经济负担。每年有超过 100 万名儿童死于 PTB 并发症，而幸存下来的儿童可能会面临发育迟缓。不幸的是，我们对与 PTB 相关的分子途径的了解仍然有限。越来越多的证据表明，DNA 甲基化（DNAm）在介导 PTB 对未来健康结果的影响中起作用。因此，全基因组 DNAm 图谱与 PTB 相关的表观基因组全关联研究（EWAS）可以帮助揭示两者之间的生物学机制。
在一个由 1019 名婴儿组成的亚洲队列中（68 名早产儿，951 名足月儿），我们使用 Infinium HumanMethylation450 阵列检查了脐带组织（n=1019）和脐带血（n=332）样本中 PTB 与全基因组 DNAm 图谱之间的关联。PTB 与脐带血中的 296 个 CpG（209 个基因）的 DNAm 显著相关（P<5.8e-7）。这些 CpG 中有超过 95%在其他 PTB/胎龄 EWAS 中在（脐带）血中得到了复制。这种复制甚至在不同种族（亚洲人、白人和非裔美国人）的人群中也是明显的。这些 296 个 CpG 中有超过三分之一在至少 4 项独立研究中得到了复制，从而确定了一组在脐带血中与 PTB 相关的稳健的表观遗传特征。除了脐带血外，对脐带组织的检测为早产儿的新生儿提供了关于其表观遗传状态的新见解。总的来说，在脐带组织中与 PTB 相关的有 994 个 CpG（608 个基因，P<3.7e-7），其中只有 10 个 CpG 在使用脐带血的分析中被识别。来自脐带组织的基因显示出与胎儿生长和发育相关的分子途径的富集，而来自脐带血的基因显示出免疫反应途径的富集。来自这两种出生组织的大量与 PTB 相关的 CpG 也与胎龄有关。
我们的研究结果为早产儿新生儿的表观遗传景观提供了新的见解，并且通过同时对多个新生儿组织进行检测，可以更全面地捕捉其状态。这两种新生儿组织都以其独特的方式具有临床相关性，在识别与 PTB 和胎龄相关的生物标志物时需要仔细考虑。
本出生队列是一项前瞻性观察性研究，旨在研究健康与疾病的发育起源，并于 2010 年 7 月 1 日在 NCT01174875 下以回顾性方式注册。
