Maternal Obesity, Fetal Genomics, and Atherosclerotic Metabolic Risk

描述(申请人提供)：越来越多的证据表明，由于肥胖相关的代谢性疾病，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性代谢风险(AMR)。然而，解释MO与AMR关联的机制仍不清楚。利用一个独特的、基于人群的出生队列数据和30年的跟踪检查，我们建议检验(1)MO和AMR的关联是否至少部分地归因于来自不同分子途径的一组候选基因中共同的母体和/或胎儿遗传变异，以及(2)母体和/或胎儿的遗传变异是否通过影响子宫内环境和胎儿生长来影响MO-AMR关系。耶路撒冷围产期研究(JPS)收集了1974-76年间出生的大量产前、围产期和产后数据。我们现在建议在现有的档案数据中增加来自母亲和子女的新的表型和基因型别数据。我们将招募一组母亲(n=1500)及其1974-76年出生的子女(n=1500)，以反映全面的MO和BW。我们将确定在30-32岁的年轻人中，母体和胎儿候选基因集的遗传变异是否通过影响子宫内生长来解释MO与AMR的关联。这些候选基因包括胰岛素敏感性和胰岛素信号、脂肪细胞稳态和下丘脑-垂体-肾上腺轴(HPA)轴，以及食欲调节神经网络。在一系列嵌套模型中，我们将在考虑其他因素(如母亲吸烟和母乳喂养)的影响后，区分可能改变子宫内环境的常见母婴遗传变异的影响，以及后代遗传变异的出生后影响和MO对成人AMR的非遗传影响。我们还将研究母体和胎儿遗传变异在AMR发生中的潜在相互作用。这项研究旨在探索几种有希望的机制途径，使用人类母体和胎儿基因组变异的测量，在MO、宫内生长和其他出生前和出生后的临床特征的背景下。这项拟议研究的长期目标是确定干预措施的潜在机械性目标，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.