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

资源匮乏环境下孕前孕产妇营养、后代 DNA 甲基化和婴儿生长

• 批准号: 10565003
• 负责人: Sarah Jean Borengasser
• 金额: $ 66.26万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565003
• 关键词: 5 year old; Acceleration; Address; Adult; Age; Anthropometry; Binding; Birth; Birth length; Body mass index; Cardiovascular Diseases; Cells; Child; Child Health; Chronic Disease; Chronology; Conceptions; Consumption; Cytosine; DNA Methylation; Data; Democratic Republic of the Congo; Dietary Intervention; Dinucleoside Phosphates; Disease; Educational Status; Epigenetic Process; Ethnic Origin; Female; Genetic Transcription; Genomic Segment; Gestational Age; Goals; Growth; Growth and Development function; Guanidines; Guatemala; Health; Health Benefit; Human; India; Individual; Infant; Life; Link; Lipids; Malignant Neoplasms; Malnutrition; Methylation; Micronutrients; Molecular; Morbidity - disease rate; Mothers; Neonatal; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutritional status; Obesity; Pakistan; Phenotype; Placenta; Pregnancy; Randomized, Controlled Trials; Reporting; Resource-limited setting; Risk; Testing; Vulnerable Populations; Woman; arm; early-life nutrition; epigenetic marker; epigenome; fetal; global health; healthspan; human capital; improved; low and middle-income countries; low income country; male; methyl group; methylation biomarker; mortality; mother nutrition; novel; nutrition; offspring; postnatal; prepregnancy; response; rural area; sex; three-arm study; treatment arm

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).

项目摘要 生长发育迟缓是一个全球性健康问题，影响约 1.49 亿 5 岁以下儿童的生活 主要发生在中低收入国家，特别是低收入国家。 特别容易受到营养不良的影响，包括微量营养素不足，这会导致 增长导致终生特技发病率和死亡率、教育成就下降以及人力流失 该提案的目标是确定孕前孕产妇营养补充剂是否可以改变。 在高生长率地区出生的婴儿中进行靶向和表观基因组范围内的 DNA 甲基化 (DNAme) DNAme 是一种调节基因转录的表观遗传机制，因此，表型 具体来说，我们将测试母亲食用少量的差异和风险。 受孕前大量脂质营养补充剂 (sqLNS) 会改变婴儿出生时及以后的 DNAme， 我们将研究这些表观遗传变化是否与生命头两年的生长有关。 称为人类亚稳态表观等位基因 (ME) 的特定基因组区域的 DNAme 是系统表观遗传的； 可以在出生时检测到的标记，并通过受孕时母亲的营养状况了解 此外，一些表观遗传时钟（Horvath、PhenoAge、Hannum）已被开发。 开发出以下估计值：1) 实际年龄，准确度≥ 96%；2) 表型年龄；3) 表观年龄； 加速（EAA）的表观遗传年龄提供了寿命和健康寿命的指示。 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，很少有研究解决这一问题。 ME 和 EAA 在生长迟缓、资源匮乏的背景下以及对先入为主的反应 该提案利用了一项已完成的随机对照试验。 （NCT01883193，女性优先，WF）来自刚果民主共和国 (DRC) 的母婴二人组， 危地马拉、印度和巴基斯坦 WF RCT 由三个治疗组组成：第 1 组 = 女性。 受孕前 ≥ 3 个月服用 sqLNS，直至分娩；第 2 组 = 女性服用相同的 sqLNS 从妊娠 12 周开始直至分娩；第 3 组 = 未消耗 sqLNS。 旨在通过 DNAme 变化增进我们对孕产妇营养以及后代健康和生长的理解： 目标 1：测试 sqLNS 的计时是否会改变称为人类亚稳态表观等位基因的特定基因组区域的 DNAme (ME) 出生时（胎盘 N = 463）和产后 3 个月（颊侧 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）。 目标 3：靶向 DNAme 谱（ME 和 EAA）和表观基因组范围的 DNAme 将预测新生儿 人体测量学和生命最初 2 年的生长（地点人体测量学 N = 463）。