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

项目摘要 发育迟缓是一个全球性的健康问题，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。非洲的发育迟缓率最高， 非洲大陆是近年来发育迟缓发生率改善最少的大陆。小 母亲倾向于生下小婴儿，但这背后的表观遗传机制 相关性知之甚少。这项研究对600名母亲胎盘中的145个印记基因进行了研究， 将测试遗传印记在代际传递中发挥作用的假设， 发育不良这项研究是创新的，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）从婴儿期开始跟踪， 从童年到初为人父母还收集了关于其父母（F0代）的数据， 后代（F2代）。这项研究结合了这些纵向数据，跨越3代， 胎盘基因的等位基因特异性表达分析。根据冲突假设5， 生长抑制基因在父本等位基因上受到抑制，而生长促进基因在父本等位基因上受到抑制。 抑制在母系等位基因上。印记的程度因人而异， 我假设这种正常的变异是发育迟缓从一个 下一代。目标1将查明母体发育迟缓和追赶性生长是否影响 145个胎盘基因的印记目的2将发现胎盘基因印记的丢失是否会导致 后代发育迟缓，通过出生时和后续随访时的仰卧位长度进行测量。目标3将测试 青春期后期城市移民的影响，以及相关的营养改善， 145个基因的印记水平。胎盘采集将由经过培训的顾问进行 这些人与研究人群属于同一种族群体，即马里中部的多贡人。的 研究中心位于班贾加拉区，是和平的;主要研究者和她的 在过去五年中，合作者每年都能访问该网站。研究团队 已经对所有协议进行了现场测试，并收集了77个胎盘，这些胎盘已经进行了部分分析 在密歇根大学的私家侦探实验室里印记基因是足够杂合的 来区分母系和父系的等位基因PCR和深度测序的结合将是 用于高精度测量压印损失。由于发育迟缓导致了广泛的健康问题， 从认知功能差到代谢综合征7，重要的是要了解它是如何 传递给下一代。这项拟议中的研究是基础科学， 最终发现预防发育迟缓及其对儿童的不利影响的干预措施和政策， 生活质量

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.