Protocol for the EMPHASIS study; epigenetic mechanisms linking maternal pre-conceptional nutrition and children's health in India and Sub-Saharan Africa.
Protocol for the EMPHASIS study; epigenetic mechanisms linking maternal pre-conceptional nutrition and children's health in India and Sub-Saharan Africa.
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DOI：
10.1186/s40795-017-0200-0
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发表时间：
2017-10-30
期刊：
影响因子：
2
通讯作者：
Fall, Caroline Hd
中科院分区：
文献类型：
--
作者：
Chandak, Giriraj R;Silver, Matt J;Fall, Caroline Hd
背景：动物研究表明，怀孕期间的营养暴露可以改变调节胎儿发育和后期疾病易感性的表观遗传标记，为解释健康和疾病的发育起源提供了一种合理的机制。人类观察性研究表明，母体孕产期饮食可以预测后代的DNA甲基化。然而，母体饮食（通过DNA甲基化变化）与后来的健康结果之间的因果关系尚未确定。强调研究（印度和撒哈拉以南非洲孕前营养与健康联系的表观遗传机制评估，ISRCTN14266771）将调查母亲参加孕前和孕期微量营养素补充的两项随机对照试验的儿童的围孕期营养与健康相关结局之间的表观遗传介导的联系。方法：最初的试验是孟买孕产妇营养项目（MMNP, ISRCTN62811278），在该项目中，印度妇女每天被提供由富含微量营养素的食物或低微量营养素的食物制成的零食（对照），以及在冈比亚农村进行的围孕期多种微量营养素补充试验（PMMST, ISRCTN13687662），在该试验中，妇女每天被提供多种微量营养素（UNIMMAP）片剂或安慰剂。在EMPHASIS研究中，将对这些妇女的孩子（约1100名5-7岁的MMNP儿童和298名7-9岁的PMMST儿童）进行DNA甲基化分析。将探讨队列特异性和跨队列效应。分配组之间的DNA甲基化差异将使用Illumina Infinium MethylationEPIC阵列，并通过对顶部hit和选定的候选位点进行pyrosequencing来鉴定。将分析DNA甲基化与健康相关表型结果之间的关联，包括出生时的体型、儿童出生后的生长、身体组成、骨骼发育、心脏代谢风险标志物（血压、血脂、血糖和胰岛素）和认知功能。通路分析将用于检测生物通路中营养敏感位点的富集情况。营养-甲基化-表型关联的因果机制将使用孟德尔随机化进行探讨。还将分析与补充无关的甲基化与表型之间的关联。结论：本研究将加深对母体营养对后代健康长期影响的表观遗传机制的理解。这将有可能为准备怀孕的母亲提供更好的营养干预，并确定后期疾病风险的早期生命生物标志物。
BACKGROUND: Animal studies have shown that nutritional exposures during pregnancy can modify epigenetic marks regulating fetal development and susceptibility to later disease, providing a plausible mechanism to explain the developmental origins of health and disease. Human observational studies have shown that maternal peri-conceptional diet predicts DNA methylation in offspring. However, a causal pathway from maternal diet, through changes in DNA methylation, to later health outcomes has yet to be established. The EMPHASIS study (Epigenetic Mechanisms linking Pre-conceptional nutrition and Health Assessed in India and Sub-Saharan Africa, ISRCTN14266771) will investigate epigenetically mediated links between peri-conceptional nutrition and health-related outcomes in children whose mothers participated in two randomized controlled trials of micronutrient supplementation before and during pregnancy.METHODS: The original trials were the Mumbai Maternal Nutrition Project (MMNP, ISRCTN62811278) in which Indian women were offered a daily snack made from micronutrient-rich foods or low-micronutrient foods (controls), and the Peri-conceptional Multiple Micronutrient Supplementation Trial (PMMST, ISRCTN13687662) in rural Gambia, in which women were offered a daily multiple micronutrient (UNIMMAP) tablet or placebo. In the EMPHASIS study, DNA methylation will be analysed in the children of these women (~1,100 children aged 5-7 y in MMNP and 298 children aged 7-9 y in PMMST). Cohort-specific and cross-cohort effects will be explored. Differences in DNA methylation between allocation groups will be identified using the Illumina Infinium MethylationEPIC array, and by pyrosequencing top hits and selected candidate loci. Associations will be analysed between DNA methylation and health-related phenotypic outcomes, including size at birth, and children's post-natal growth, body composition, skeletal development, cardio-metabolic risk markers (blood pressure, serum lipids, plasma glucose and insulin) and cognitive function. Pathways analysis will be used to test for enrichment of nutrition-sensitive loci in biological pathways. Causal mechanisms for nutrition-methylation-phenotype associations will be explored using Mendelian Randomization. Associations between methylation unrelated to supplementation and phenotypes will also be analysed.CONCLUSION: The study will increase understanding of the epigenetic mechanisms underpinning the long-term impact of maternal nutrition on offspring health. It will potentially lead to better nutritional interventions for mothers preparing for pregnancy, and to identification of early life biomarkers of later disease risk.