Maternal Obesity, Fetal Genomics, and Atherosclerotic Metabolic Risk

描述（由申请人提供）：越来越多的证据表明，由于肥胖相关的代谢疾病，如糖尿病、高胆固醇血症和高血压，母亲肥胖（MO）会影响胎儿发育和成人动脉粥样硬化代谢风险（AMR）。然而，MO与AMR相关的机制仍然未知。利用一项独特的、基于人群的出生队列数据和30年的随访检查，我们建议检查(1)MO和AMR的关联是否至少部分归因于来自不同分子途径的一组候选基因的常见母体和/或胎儿遗传变异，以及(2)母体和/或胎儿遗传变异是否通过对子宫内环境和胎儿生长的影响来影响MO- AMR的关系。耶路撒冷围产期研究（JPS）收集了1974-76年出生的大量产前、围产期和产后数据。我们现在建议在现有的档案数据中添加新的来自母亲和后代的表型和基因型数据。我们将招募一个亚队列的母亲（n =1500）和她们在1974-76年出生的后代（n =1500），反映了MO和BW的全部范围。我们将通过对子宫内生长的影响，确定30-32岁年轻成人中胰岛素敏感性和胰岛素信号、脂肪细胞稳态和下丘脑-垂体-肾上腺（HPA）轴以及食欲调节神经网络等分子通路中一系列候选基因的母体和胎儿遗传变异是否与MO与AMR相关。在一系列嵌套模型中，我们将区分有可能改变子宫内环境的常见母体和胎儿遗传变异的影响，以及后代遗传变异的产后影响和MO对成人AMR的非遗传影响，同时考虑到其他因素的影响，如母亲吸烟和母乳喂养。我们还将研究MO与母体和胎儿遗传变异对AMR发展的潜在相互作用。该研究旨在探索几种有希望的机制途径，利用人类母体和胎儿基因组变异的测量，在MO，子宫内生长和其他产前和产后临床特征的背景下。本研究的长期目标是确定干预措施的潜在机制靶点，以防止MO对子宫内环境和成人AMR的影响。

DESCRIPTION (provided by applicant): There is mounting evidence that maternal obesity (MO) influences both fetal development and adult atherosclerotic metabolic risk (AMR), due to obesity-related metabolic diseases, such as diabetes, hypercholesterolemia, and high blood pressure. However, the mechanisms that account for the associations of MO with AMR remain unknown. Using data from a unique, population-based, birth cohort and a 30-year follow-up examination, we propose to examine (1) whether the association of MO and AMR is due, at least in part, to common maternal and/or fetal genetic variation in a set of candidate genes from distinct molecular pathways, and (2) whether maternal and/or fetal genetic variation influences the MO- AMR relation through an effect on the intra-uterine environment and fetal growth. The Jerusalem Perinatal Study (JPS) collected extensive prenatal, perinatal, and postnatal data from births from 1974-76. We now propose to add new phenotypic and genotypic data from mothers and offspring to the existing archival data. We will recruit a sub-cohort of mothers (n =1500) and their offspring born from 1974-76 (n = 1500), reflecting the full range of MO and BW. We will determine whether maternal and fetal genetic variation in sets of candidate genes in molecular pathways, such as insulin sensitivity and insulin signaling, adipocyte homeostasis and hypothalamic-pituitary-adrenal (HPA) axis, and the appetite regulatory neural network, account for the associations of MO with AMR in young adults, ages 30-32, through an effect on intra- uterine growth. In a series of nested models, we will distinguish the effects of common maternal and fetal genetic variation that has the potential to alter the intra-uterine environment, from post-natal effects of offspring genetic variation and non-genetic effects of MO on adult AMR, after taking into account the effects of other factors, such as maternal smoking and breast feeding. We also will examine potential interactions of MO with maternal and fetal genetic variation on the development of AMR. The research is designed to explore several promising mechanistic pathways, using measures of human maternal and fetal genomic variation, in the context of MO, intra-uterine growth, and other pre- and post-natal clinical characteristics. The long-term goals of the proposed study are to identify potential mechanistic targets for interventions to prevent the consequences of MO on the intra-uterine environment and adult AMR.