MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, United Kingdom.
Genomic Research on Complex Diseases (GRC Group), CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.
Am J Clin Nutr. 2020 Oct 1;112(4):1099-1113. doi: 10.1093/ajcn/nqaa193.
Maternal nutrition in pregnancy has been linked to offspring health in early and later life, with changes to DNA methylation (DNAm) proposed as a mediating mechanism.
We investigated intervention-associated DNAm changes in children whose mothers participated in 2 randomized controlled trials of micronutrient supplementation before and during pregnancy, as part of the EMPHASIS (Epigenetic Mechanisms linking Preconceptional nutrition and Health Assessed in India and sub-Saharan Africa) study (ISRCTN14266771).
We conducted epigenome-wide association studies with blood samples from Indian (n = 698) and Gambian (n = 293) children using the Illumina EPIC array and a targeted study of selected loci not on the array. The Indian micronutrient intervention was food based, whereas the Gambian intervention was a micronutrient tablet.
We identified 6 differentially methylated CpGs in Gambians [2.5-5.0% reduction in intervention group, all false discovery rate (FDR) <5%], the majority mapping to ESM1, which also represented a strong signal in regional analysis. One CpG passed FDR <5% in the Indian cohort, but overall effect sizes were small (<1%) and did not have the characteristics of a robust signature. We also found strong evidence for enrichment of metastable epialleles among subthreshold signals in the Gambian analysis. This supports the notion that multiple methylation loci are influenced by micronutrient supplementation in the early embryo.
Maternal preconceptional and pregnancy micronutrient supplementation may alter DNAm in children measured at 7-9 y. Multiple factors, including differences between the nature of the intervention, participants, and settings, are likely to have contributed to the lack of replication in the Indian cohort. Potential links to phenotypic outcomes will be explored in the next stage of the EMPHASIS study.
孕期母体营养与后代生命早期和后期的健康有关，DNA 甲基化（DNAm）的变化被认为是一种介导机制。
我们研究了母亲在妊娠前和妊娠期间参加了两项微量营养素补充随机对照试验的儿童的干预相关 DNAm 变化，这是 EMPHASIS（印度和撒哈拉以南非洲孕前营养与健康的表观遗传机制）研究的一部分（ISRCTN87657174）。
我们使用 Illumina EPIC 阵列对来自印度（n=698）和冈比亚（n=293）儿童的血液样本进行全基因组关联研究，并对未在阵列上的选定基因座进行靶向研究。印度的微量营养素干预是基于食物的，而冈比亚的干预是一种微量营养素片剂。
我们在冈比亚发现了 6 个差异甲基化 CpG [干预组减少 2.5-5.0%，所有错误发现率（FDR）<5%]，大多数位于 ESM1 上，该区域在区域分析中也有强烈信号。在印度队列中，有一个 CpG 通过了 FDR<5%，但总体效应大小较小（<1%），并且没有稳健特征的特征。我们还在冈比亚分析中发现了亚阈值信号中存在不稳定表等位基因富集的强烈证据。这支持了这样一种观点，即早期胚胎中的微量营养素补充可能会影响多个 DNAm 位点。
母亲孕前和孕期的微量营养素补充可能会改变 7-9 岁儿童的 DNAm。多种因素，包括干预性质、参与者和环境的差异，可能导致印度队列缺乏复制。在下一阶段的 EMPHASIS 研究中，将探索与表型结果的潜在联系。
