Effect of the Placental Epigenome on Stunting in a Longitudinal African Cohort

胎盘表观基因组对非洲纵向队列发育迟缓的影响

• 批准号: 9518998
• 负责人: Beverly Ilse Strassmann
• 金额: $ 61.03万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-16 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9518998
• 关键词: 20 year old; 5 year old; Adolescence; Adult; Adverse effects; Affect; Africa; African; Age; Alleles; Anthropometry; Basic Science; Birth; Child; Childhood; Cities; Collection; Conflict (Psychology); Data; Development; Disease; Environment; Epigenetic Process; Ethnic group; Fathers; Fetal Growth; Fetus; First Births; Food; Future; Generations; Genes; Genome; Genomic Imprinting; Growth; Health; Height; Human; Hypertension; IGF2 gene; Impairment; Individual; Intervention; Laboratories; Length; Life Experience; Light; Low Birth Weight Infant; Mali; Measures; Metabolic; Michigan; Mothers; Natural experiment; Nutritional status; Organ; Organ Size; Ovum Donor; Parents; Pathology; Placenta; Play; Policies; Population; Positioning Attribute; Pregnancy; Prevalence; Principal Investigator; Property; Prospective cohort study; Protocols documentation; Puberty; Quality of life; Reporting; Repression; Research; Research Design; Resource Allocation; Resources; Role; Rural; Sampling; Secure; Site; Site Visit; Statistical Models; Supination; Testing; Tissues; Training; Universities; Variant; base; boys; cognitive function; cohort; deep sequencing; diabetes risk; early childhood; epidemiology study; epigenome; expectation; field study; follow-up; girls; global health; imprint; infancy; innovation; intergenerational; low and middle-income countries; maternal imprint; migration; molecular marker; next generation; nutrition; nutritional supplementation; offspring; paternal imprint; predictive test; prevent; study population; theories; transmission process

Project Summary Stunting is a global health problem that is common in low and middle-income countries where one third of children under 5 years of age are affected6. Africa has the highest rates of stunting and is the continent that has shown the least improvement in the prevalence of stunting in recent years. Small mothers tend to give birth to small babies, but the epigenetic mechanisms that underlie this correlation are poorly understood. This study of 145 imprinted genes in placentas from 600 mothers will test the hypothesis that genetic imprinting plays a role in the inter-generational transmission of stunting. This research is innovative because it takes advantage of a prospective cohort study of a rural African population in which 1144 subjects (F1 generation) are followed from infancy, through childhood, to first parenthood. Data are also being gathered on their parents (F0 generation) and offspring (F2 generation). This study combines these longitudinal data, spanning 3 generations, with the analysis of allele-specific expression of placental genes. According to the conflict hypothesis5, growth-inhibiting genes are repressed on the paternal alleles and growth-promoting genes are repressed on the maternal alleles. The degree of imprinting varies between individuals and we hypothesize that this normal variation is the mechanism by which stunting is transmitted from one generation to the next. Aim 1 will find out if maternal stunting and catch-up growth affect the level of imprinting in 145 placental genes. Aim 2 will find out if loss of imprinting of placental genes leads to offspring stunting, as measured by supine length at birth and at later follow-up. Aim 3 will test the effect of urban migration in late adolescence, and the associated improvement in nutrition, on the level of imprinting in 145 genes. The placental collections will be carried out by trained consultants who belong to the same ethnic group as the study population, namely the Dogon of central Mali. The study site is located in the District of Bandiagara and is peaceful; the principal investigator and her collaborators have been able to visit the site every year for the past five years. The research team has field-tested all the protocols and collected 77 placentas, which have already been partly analyzed in the PI's laboratory at the University of Michigan. The imprinted genes are sufficiently heterozygous to differentiate maternal from paternal alleles. A combination of PCR and deep sequencing will be used to measure loss of imprinting with high accuracy. As stunting leads to a wide array of health problems from poor cognitive function to metabolic syndrome7, it is important to understand how it is transmitted to the next generation. The proposed study is basic science that is necessary for the eventual discovery of interventions and policies that prevent stunting and its adverse effects on the quality of life.

项目概要 发育迟缓是一种全球性健康问题，在低收入和中等收入国家很常见。 三分之一的 5 岁以下儿童受到影响6。非洲是发育迟缓率最高的国家 近年来发育迟缓发生率改善最少的大陆。小的 母亲倾向于生出小婴儿，但这背后的表观遗传机制 相关性尚不清楚。这项研究对 600 名母亲胎盘中的 145 个印记基因进行了研究 将检验遗传印记在代际传播中发挥作用的假设 发育迟缓。这项研究具有创新性，因为它利用了一项前瞻性队列研究 非洲农村人口，其中 1144 名受试者（F1 代）从婴儿期开始接受跟踪调查，直至 童年，到第一次为人父母。他们的父母（F0 代）和 后代（F2代）。这项研究结合了这些跨越 3 代人的纵向数据， 胎盘基因等位基因特异性表达的分析。根据冲突假设5， 生长抑制基因在父系等位基因上受到抑制，而生长促进基因则在父系等位基因上受到抑制。 母体等位基因受到抑制。印记的程度因人而异 假设这种正常变异是发育迟缓从一个人传播的机制 一代又一代。目标 1 将查明母亲发育迟缓和追赶性生长是否会影响 145 个胎盘基因的印记。目标 2 将查明胎盘基因印记的丧失是否会导致 后代发育迟缓，通过出生时和后续随访时的仰卧长度来测量。目标 3 将测试 青春期后期城市迁移以及相关的营养改善对 145个基因的印记水平。胎盘采集将由经过培训的顾问进行 他们与研究人群属于同一民族，即马里中部的多贡人。这 研究地点位于班迪亚加拉区，环境安静；首席研究员和她 在过去的五年里，合作者每年都能够访问该网站。研究团队 已对所有协议进行了现场测试并收集了 77 个胎盘，并已对其进行了部分分析 在 PI 位于密歇根大学的实验室中。印记基因具有足够的杂合性 区分母本和父本等位基因。 PCR 和深度测序相结合 用于高精度测量压印损失。发育迟缓会导致一系列健康问题 从认知功能差到代谢综合征7等问题，了解它是如何发生的很重要 遗传给下一代。拟议的研究是必要的基础科学 最终发现预防发育迟缓及其对人类不利影响的干预措施和政策 生活质量。