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的健康问题，影响到约1.49亿5岁以下儿童的生活， 主要是在低收入和中等收入国家，特别是低收入国家。母亲和婴儿 特别容易受到营养不良的影响，包括微量营养素不足， 发育迟缓导致终生发病和死亡，教育成就降低， 资本这项提案的目的是确定孕前母亲营养补充剂是否能改变 在生长速度快的地区出生的婴儿中进行靶向和表观基因组DNA甲基化（DNAme） 发育不良DNAme是调节基因转录的表观遗传机制，因此， 差异和非传染性疾病的风险。具体来说，我们将测试母亲是否摄入少量 在怀孕前大量的基于脂质的营养补充剂（sqLNS）改变了出生时及以后的婴儿DNA， 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 称为人类亚稳定表观等位基因（ME）的特定基因组区域的DNAme; ME是系统性表观遗传的 出生时可以检测到的标记，并且已知在怀孕时母亲的营养状况会改变这些标记， 低资源设置。此外，几个表观遗传时钟（Horvath，PhenoAge，Hannum）已被 开发了估计：1）实际年龄，准确度≥ 96%; 2）表型年龄; 3）表观遗传年龄 加速度（EAA）。表观遗传年龄的估计提供了生命和健康寿命的指标。肥胖， 心血管疾病、癌症和2型糖尿病已被证明与 EAA增加，可能会减少寿命和健康寿命。然而，很少有研究涉及 在生长发育迟缓、低资源背景下的ME和EAA，以及对偏见的回应 产妇营养干预。该提案利用了一项已完成的随机对照试验 （NCT 01883193，妇女优先，WF）在来自刚果民主共和国（DRC）的母婴二对体中， 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 在受孕前≥ 3个月使用sqLNS直至分娩;组2 =女性使用相同的sqLNS 从12周进食开始直至分娩;组3 =不消耗sqLNS。我们提议下列 旨在通过DNAme变化来促进我们对母体营养和后代健康和生长的理解： 目的1：测试sqLNS的时机是否改变了称为人类亚稳态表观等位基因的特定基因组区域的DNAme (MEs)在出生时（胎盘N = 463）和出生后3个月（口腔N = 391）使用EPIC 850 K阵列。 目的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谱（MEs & EAA）和表观基因组范围的DNAme将预测新生儿 出生后头2年的人体测量和生长（胎盘N = 463）。