A longitudinal study of stunting and growth modulating genes in human placentas

描述（由申请人提供）：发育迟缓是一个全球健康问题，在低收入和中等收入国家很常见，其中三分之一的5岁以下儿童受到影响。非洲发育迟缓率最高，也是近年来发育迟缓率改善最少的大陆2。身材矮小的母亲往往生出身材矮小的婴儿，但人们对这种相关性背后的表观遗传机制知之甚少。这项对来自[200]母亲的胎盘中30个印迹基因的探索性研究将检验遗传印迹在发育迟缓的代际传播中起作用的假设。这项拟议的研究具有创新性，因为它利用了一项对非洲农村人口的前瞻性队列研究，在这项研究中，我们跟踪了600名女孩（F1一代），从婴儿期到童年，直到她们的第一次生育。还收集了这些受试者的父母（F0）和后代（F2）的数据。我们将这些跨越3代的纵向数据与胎盘基因的等位基因特异性表达分析结合起来，处于一个独特的位置。[根据冲突假说，生长抑制基因在父本等位基因上受到抑制，而生长促进基因在母本等位基因上受到抑制。]印记的程度在个体之间是不同的，我们假设这种正常的变异是发育迟缓从一代传递到下一代的机制。目的1将发现母体发育迟缓是否与胎盘中促生长基因（如IGF2）的高水平印迹有关。目的2评估发育不良影响的关键窗口，以及发育不良与赶超生长之间的相互作用。目的3将发现胎盘中促进生长基因的抑制增加是否会导致后代发育迟缓，这是通过出生时和一个月大时的仰卧长度来衡量的。胎盘收集将由我们的马里合作者进行，包括两名助产士和一名长期居住在[马里中部班迪亚加拉区]研究地点的医院助理。这里很和平，距离政治局势紧张的基达尔500多英里。研究小组对所有方案进行了实地测试，并收集了22个胎盘，其中5个已由PI在密歇根大学的实验室进行了分析。我们将使用PCR和深度测序相结合的方法来高精度地测量印迹的损失。由于发育迟缓会导致一系列健康问题，从认知功能低下到代谢综合征，因此了解它是如何遗传给下一代是很重要的。拟议的研究是基础科学，对于最终发现预防发育迟缓及其对生活质量的不利影响的干预措施和政策是必要的。

DESCRIPTION (provided by applicant): 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 affected1. Africa has the highest rates of stunting and is the continent that has shown the least improvement in the prevalence of stunting in recent years2. Small mothers tend to give birth to small babies3, but the epigenetic mechanisms that underlie this correlation are poorly understood. This exploratory study of 30 imprinted genes in placentas from [200] mothers will test the hypothesis that genetic imprinting plays a role in the inter-generational transmission of stunting. The proposed study is innovative because it takes advantage of a prospective cohort study of a rural African population in which we are following 600 girls (F1 generation) from infancy, through childhood, to their first birth. Data are also being gathered on the parents (F0) and offspring (F2) of these subjects. We are in a unique position to combine these longitudinal data, spanning 3 generations, with the analysis of allele-specific expression of placental genes. [According to the conflict hypothesis4, 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 is associated with higher levels of placental imprinting of growth promoting genes such as IGF2. Aim 2 assesses the critical windows at which stunting matters, and the interaction between stunting and catch up growth. Aim 3 will find out if increased repression of growth promoting genes in the placenta leads to offspring stunting, as measured by supine length at birth and at age one month.] The placental collections will be carried out by our Malian collaborators, including two mid-wives and a hospital assistant who reside permanently at the study site [in the District of Bandiagara in central Mali. This site is peaceful and more than 500 miles from Kidal, an area of political tension. The research team has field-tested all the protocols and collected 22 placentas, 5 of which have been analyzed by the PI's laboratory at the University of Michigan.] We will use a combination of PCR and deep sequencing to measure loss of imprinting with high accuracy. As stunting leads to a wide range of health problems from poor cognitive function to metabolic syndrome5, 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.