Preconception Maternal Nutrition, Offspring DNA Methylation, and Infant Growth in Low Resource Settings

项目摘要 生长发育迟缓是一个影响约1.49亿5岁以下儿童的全球健康问题 主要是在中低收入国家，特别是低收入国家。母亲和婴儿都是 特别容易受到营养不良的影响，包括微量营养素不足，这有助于 发育迟缓导致终生发病率和死亡率、教育程度降低和人类死亡 资本。这项提案的目的是确定先入为主的孕妇营养补充剂是否会改变 出生在高增长率地区的婴儿中的靶向和表观基因组DNA甲基化(DNAME) 发育迟缓。DNAME是一种表观遗传机制，它调节基因转录，因此，表型 非传染性疾病的差异和风险。具体地说，我们将测试孕妇的消费量是否很小 怀孕前大量的基于脂质的营养补充剂(SQLNS)改变了出生时和以后的婴儿DNAME， 以及这些表观遗传变化是否与生命头两年的生长有关。我们将研究 称为人类亚稳态表观等位基因(MES)的特定基因组区域的DNA；MES是系统表观遗传学 可在出生时检测到的标记，并已知在怀孕时会因母亲的营养状况而改变 资源设置较低。此外，几个表观遗传钟(Horvath，PhenoAge，Hannum)已经 建立了这样的估计：1)年代学年龄，≥96%的准确率；2)表型年龄；3)表观遗传年龄 加速(EAA)。表观遗传年龄的估计提供了寿命和健康跨度的指标。肥胖， 心血管疾病、癌症和2型糖尿病已被证明与 EAA增加，可能会缩短寿命和健康寿命。然而，很少有研究解决这个问题 MES和EAA在生长发育迟缓、低资源环境和应对先入为主的背景下 孕产妇营养干预。该方案利用一项已完成的随机对照试验 (NCT01883193，妇女优先，WF)，来自刚果民主共和国的母婴二人组， 危地马拉、印度和巴基斯坦。WF随机对照试验由三个治疗分支组成：AR1=妇女 在怀孕前3个月至分娩前摄入SQLNS≥；ARM 2=女性摄入相同的SQLNS 从12周开始，直到分娩；ARM 3=没有消耗任何SQLNS。我们提出以下建议 旨在通过DNAME更改来促进我们对母亲营养以及后代健康和生长的理解： 目的1：测试SQLNS的时间是否改变称为人类亚稳态表位基因的特定基因组区域的DNAME (MES)出生时(胎盘N=463)和出生后3个月(颊N=391)使用EPIC 850K阵列。 目标2：确定影响婴儿表观遗传和胎龄加速的母婴因素 (GAA，胎盘N=463)。 目的3：靶向DNAME图谱(MES和EAA)和表观基因组DNAME将预测新生儿 出生前2年的人体测量和生长(胎盘N=463)。

PROJECT ABSTRACT Growth stunting is a global health problem that impacts ~149 million children under 5 years of age living primarily in low-and-middle income-countries, particularly low-income countries. Mothers and infants are particularly vulnerable to the impacts of malnutrition, including inadequacy of micronutrients which contributes to stunted growth resulting in life-long morbidity and mortality, lower education achievement, and loss of human capital. The goal of this proposal is to determine if a preconception maternal nutrition supplement can alter targeted and epigenome-wide DNA methylation (DNAme) in infants born in regions prone to high rates of growth stunting. DNAme is an epigenetic mechanism that regulates gene transcription, and thus, phenotypical differences and risk for noncommunicable diseases. Specifically, we will test if maternal consumption of a small quantity lipid-based nutrient supplement (sqLNS) prior to conception alters infant DNAme at birth and beyond, and if these epigenetic changes are associated with growth during the first two years of life. We will examine DNAme of specific genomic regions called human metastable epialleles (MEs); MEs are systemic epigenetic marks that can be detected at birth and known to be altered by maternal nutritional status at conception in low resource settings. In addition, several epigenetic clocks (Horvath, PhenoAge, Hannum) have been developed that estimate: 1) chronological age with ≥ 96% accuracy; 2) phenotypic age; and 3) epigenetic age acceleration (EAA). Estimates of epigenetic age provide indications of life and health span. Obesity, cardiovascular disease, cancers, and type 2 diabetes mellitus have been shown to be strongly associated with increased EAA, potentially reducing life and health span. However, there are a paucity of studies addressing MEs and EAA in the context of growth stunting, low resource settings, and in response to a preconception maternal nutritional intervention. This proposal leverages a completed randomized controlled trial (NCT01883193, Women First, WF) in mother-infant dyads from the Democratic Republic of the Congo (DRC), Guatemala, India, and Pakistan. The WF RCT was comprised of three treatment arms: Arm 1 = women consumed sqLNS ≥ 3 months prior to conception until delivery; Arm 2 = women consumed the same sqLNS commencing at 12 weeks gestion until delivery; and Arm 3 = no sqLNS was consumed. We propose the following aims to advance our understanding of maternal nutrition and offspring health and growth via DNAme changes: Aim 1: Test if timing of sqLNS alters DNAme of specific genomic regions called human metastable epialleles (MEs) at birth (placenta N = 463) and 3 months postnatally (buccal N = 391) using EPIC 850K arrays. Aim 2: Determine maternal and infant factors that impact infant epigenetic and gestational age acceleration (GAA, placenta N =463). Aim 3: Targeted DNAme profiles (MEs & EAA) and epigenome-wide DNAme will be predictive of neonatal anthropometry and growth in the first 2 years of life (placenta N = 463).