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; 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 增长阻滞是一个全球健康问题，影响约1.49亿5岁以下的儿童 首先在中低收入国家，尤其是低收入国家。母亲和婴儿是 特别容易受到营养不良的影响，包括微量营养素的不足，这有助于 发育不良的增长导致终身发病率和死亡率，较低的教育成就以及人类的丧失 首都。该提议的目的是确定先入概念的材料营养是否可以改变 靶向和表观基因组范围内的DNA甲基化（DNAME），在易于生长率的地区出生 发育迟缓。 dname是一种调节基因转录的表观遗传机制，因此表型 非通信疾病的差异和风险。具体而言，我们将测试孕产妇的消费量是否小 概念之前的基于数量脂质的营养补充剂（SQLN）会改变婴儿在出生时及以后的婴儿dname， 如果这些表观遗传变化与生命的头两年有关。我们将检查 特定基因组区域的dname称为人亚稳态（MES）； MES是系统的表观遗传学 可以在出生时检测到的标记，并知道会因孕产妇营养状况而改变 资源设置低。此外，几个表观遗传时钟（horvath，phenoage，hannum）已经 开发了该估计值：1）准确度≥96％的年代年龄； 2）表型年龄； 3）表观遗传时代 加速度（EAA）。表观遗传年龄的估计提供了寿命和健康跨度的指示。肥胖， 心血管疾病，癌症和2型糖尿病已被证明与 EAA增加，可能会降低寿命和健康范围。但是，解决方案的研究很少 在增长阻碍，资源低下以及对先入后人的反应下，MES和EAA 孕产妇营养干预。该建议利用完整的随机对照试验 （NCT01883193，妇女首先，WF）刚果民主共和国（DRC）的母亲二元组， 危地马拉，印度和巴基斯坦。 WF RCT完成了三个治疗臂：ARM 1 =女性 在概念前3个月消耗≥3个月的SQLN;手臂2 =女性消耗相同的SQLN 在妊娠12周之前粉碎到交货；手臂3 =不消耗SQLN。我们提出以下内容 旨在通过DNAME变化来促进我们对孕产妇营养以及后代健康和成长的理解： AIM 1：测试SQLNS的时间是否改变了称为人亚稳态的特定基因组区域的DNAME （MES）出生时（Placeta n = 463）和使用Epic 850k阵列的产后3个月（颊n = 391）。 目标2：确定影响婴儿表观遗传和胎龄加速的材料和婴儿因素 （GAA，胎盘n = 463）。 AIM 3：有针对性的DNAME轮廓（MES＆EAA）和范围内基因组的Dname将预测新生儿 人体测量法和生命的头两年（plapeta n = 463）。